Research

Front Immunol. 2021 Mar 11;12:654406. doi: 10.3389/fimmu.2021.654406. eCollection 2021.

ABSTRACT

Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled. Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions. Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed. Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection. Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

PMID:33777053 | PMC:PMC7991083 | DOI:10.3389/fimmu.2021.654406

Clin Transl Immunology. 2021 Mar 22;10(3):e1266. doi: 10.1002/cti2.1266. eCollection 2021.

ABSTRACT

OBJECTIVES: The present phenotype-based disease classification causes ambiguity in diagnosing and determining timely, effective treatment options for primary immunodeficiency (PID). In this study, we aimed to examine the characteristics of early-onset PID and proposed a JAK-STATopathy subgroup based on their molecular defects.

METHODS: We reviewed 72 patients (< 100 days) retrospectively. These patients exhibited various immune-related phenotypes and received a definitive molecular diagnosis by next-generation sequencing (NGS)-based tests. We evaluated the PID-causing genes and clinical parameters. We assessed the genes that shared the JAK-STAT signalling pathway. We also examined the potential high risks related to the 180-day death rate.

RESULTS: We identified PID disorders in 25 patients (34.72%, 25/72). The 180-day mortality was 26.39% (19/72). Early onset of disease (cut-off value of 3.5 days of age) was associated with a high 180-day death rate (P = 0.009). Combined immunodeficiency with associated or syndromic features comprised the most common PID class (60.00%, 15/25). Patients who presented life-threatening infections were most likely to exhibit PID (odds ratio [OR] = 2.864; 95% confidence interval [CI]: 1.047-7.836). Twelve out of 72 patients shared JAK-STAT pathway defects. Seven JAK-STATopathy patients were categorised as PID. They were admitted to NICUs as immunological emergencies. Most of them experienced severe infections and thrombocytopenia, with 4 succumbing to an early death.

CONCLUSIONS: This study confirmed that NGS can be utilised as an aetiological diagnostic method of complex immune-related conditions in early life. Through the classification of PID as pathway-based subtypes, we see an opportunity to dissect the heterogeneity and to direct targeted therapies.

PMID:33777394 | PMC:PMC7984964 | DOI:10.1002/cti2.1266

Respir Med Case Rep. 2021;33:101397. doi: 10.1016/j.rmcr.2021.101397. Epub 2021 Mar 24.

ABSTRACT

BACKGROUND: COVID-19 is a potentially critical infectious disease. Inflammatory response and disease severity may vary according to immune system status. The aim of this case series is to investigate different presentation of COVID-19 in immunocompromised patients.

METHODS: this is a single centre case series about 17 immunocompromised patients admitted to our respiratory department during the recent COVID-19 pandemic. White blood cell count, C reactive protein, interleukin 6, lymphocytic subpopulation count (CD4⁺, CD8⁺, CD20⁺) and immunoglobulin count (IgG, IgM, IgA) were measured at hospitalization.

RESULTS: the most common causes of immunosuppression observed in our severe COVID-19 population are hematological malignancies, immunosuppressant drugs for transplant, primary immunodeficiency and inflammatory bowel disease. Onset symptoms were fever (88%), cough (53%), dyspnoea (24%), asthenia (35%), anosmia and/or ageusia (17%), expectoration (12%). Compared to benign conditions, patients with malignancies show a lower lymphocytic count (490 vs 1100 cells/uL) and higher interleukin 6 (33 vs 13 pg/mL).

CONCLUSIONS: immunocompromised patients are at risk of adverse outcome from COVID-19. Hematological malignancies and anti-CD20 therapies induce a high risk. Primary immunodeficiency and classical immunosuppressant such as calcineurin inhibitors and antimetabolites share an intermediate risk.

PMID:33777690 | PMC:PMC7987579 | DOI:10.1016/j.rmcr.2021.101397

Front Med (Lausanne). 2021 Mar 12;8:665475. doi: 10.3389/fmed.2021.665475. eCollection 2021.

ABSTRACT

Lupus nephritis in the context of Systemic Lupus Erythematosus (SLE) is characterized by an unpredicted course with remissions and flare-ups. Among others, it remains a significant cause of end-stage kidney disease (ESKD) in relatively young patients. Therapeutic regimens with newer immunosuppressive agents have been introduced in order to control SLE clinical manifestations more efficiently and limit organ damage induced by immune complex formation and sustained inflammation. Treatment is usually long-term, and the cumulative impact of immunosuppression is expressed through the increased frequency of infections and neoplasms. However, if the observed immunity dysregulation is secondary and pharmaceutically induced or there is a pre-existing, primary immunodeficiency that shares common pathogenetic pathways with SLE’s autoimmunity is not always clear. Herein, we present the case of a 39-year-old woman, that reached ESKD due to lupus nephritis. After an upper respiratory cytomegalovirus (CMV) infection and concomitant CMV reactivations the investigation revealed significant immunodeficiency. Not long after the initiation of intravenous immunoglobulin (IVIG) administration, patient received a cadaveric kidney transplant. IVIG was continued along with standard immunosuppression so that both recurrent infections and allograft rejection are avoided. Patient is closely monitored, and her post-transplant course is remarkably satisfying so far. ESKD patients with immunodeficiency syndromes should not be excluded by definition from kidney transplantation.

PMID:33777986 | PMC:PMC7994764 | DOI:10.3389/fmed.2021.665475

Pediatr Allergy Immunol. 2021 Mar 27. doi: 10.1111/pai.13510. Online ahead of print.

ABSTRACT

BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunological, and molecular data of monogenic IEI patients with and without autoimmune manifestations.

METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data.

RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity.

CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next generation sequencing (due to phenocopies of IEI genes) to discover responsible genes for the immune dysregulation at an early stage of the disease.

PMID:33774840 | DOI:10.1111/pai.13510

Int Immunopharmacol. 2021 Mar 24;95:107565. doi: 10.1016/j.intimp.2021.107565. Online ahead of print.

ABSTRACT

Rituximab (RTX), as a monoclonal antibody-based immunotherapeutic intervention targeting CD20 on B cells, has proven efficacy in the treatment of patients with some immune-mediated diseases. In the present review, we provided information on the immunobiological mechanisms of signaling for RTX and its clinical applications, according to the immune-pathophysiology involved in the microenvironment of multiple diseases. We highlighted combination therapy, dose schedules, and laboratory monitoring, as well as the associated common and rare side effects to avoid. We also discussed the efficacy and safety of RTX-based therapeutic strategies and whether RTX therapy can be used as a promising treatment regimen for autoimmune diseases, primary immunodeficiency diseases, and malignancies. Our review highlights and supports the importance of collaboration between basic medical researchers and clinical specialists when considering the use of RTX in the treatment of various immune-mediated disorders.

PMID:33773205 | DOI:10.1016/j.intimp.2021.107565

Eur J Clin Pharmacol. 2021 Mar 27. doi: 10.1007/s00228-021-03102-3. Online ahead of print.

ABSTRACT

PURPOSE: Nasal irrigation or nebulizing aerosol of isotonic or hypertonic saline is a traditional method for respiratory or nasal care. A recent small study in outpatients with COVID-19 without acute respiratory distress syndrome suggests substantial symptom resolution. We therefore analyzed pharmacological/pharmacodynamic effects of isotonic or hypertonic saline, relevant to SARS-CoV-2 infection and respiratory care.

METHODS: Mixed search method.

RESULTS: Due to its wetting properties, saline achieves an improved spreading of alveolar lining fluid and has been shown to reduce bio-aerosols and viral load. Saline provides moisture to respiratory epithelia and gels mucus, promotes ciliary beating, and improves mucociliary clearance. Coronaviruses and SARS-CoV-2 damage ciliated epithelium in the nose and airways. Saline inhibits SARS-CoV-2 replication in Vero cells; possible interactions involve the viral ACE2-entry mechanism (chloride-dependent ACE2 configuration), furin and 3CLpro (inhibition by NaCl), and the sodium channel ENaC. Saline shifts myeloperoxidase activity in epithelial or phagocytic cells to produce hypochlorous acid. Clinically, nasal or respiratory airway care with saline reduces symptoms of seasonal coronaviruses and other common cold viruses. Its use as aerosol reduces hospitalization rates for bronchiolitis in children. Preliminary data suggest symptom reduction in symptomatic COVID-19 patients if saline is initiated within 48 h of symptom onset.

CONCLUSIONS: Saline interacts at various levels relevant to nasal or respiratory hygiene (nasal irrigation, gargling or aerosol). If used from the onset of common cold symptoms, it may represent a useful add-on to first-line interventions for COVID-19. Formal evaluation in mild COVID-19 is desirable as to establish efficacy and optimal treatment regimens.

PMID:33772626 | DOI:10.1007/s00228-021-03102-3

Science. 2021 Mar 26;371(6536):1309-1310. doi: 10.1126/science.abg8077.

NO ABSTRACT

PMID:33766873 | DOI:10.1126/science.abg8077

Inflamm Regen. 2021 Mar 25;41(1):9. doi: 10.1186/s41232-021-00159-6.

ABSTRACT

Primary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

PMID:33766139 | DOI:10.1186/s41232-021-00159-6

J Allergy Clin Immunol Pract. 2021 Mar 22:S2213-2198(21)00328-7. doi: 10.1016/j.jaip.2021.03.021. Online ahead of print.

NO ABSTRACT

PMID:33766581 | DOI:10.1016/j.jaip.2021.03.021