Manish Butte

Front Immunol. 2022 Sep 29;13:1025343. doi: 10.3389/fimmu.2022.1025343. eCollection 2022.

ABSTRACT

Two types of autoimmune hepatitis (AIH) are recognized; AIH-1 is characterized by the presence of anti-nuclear and/or anti-smooth muscle autoantibodies, while AIH-2 is associated with the presence of anti-Liver kidney microsome and/or anti-Liver Cytosol antibodies. The autoantigens targeted by AIH-2 autoantibodies are the cytochrome P450 2D6 and Formiminotransferase-cyclodeaminase for anti-LKM1 and anti-LC1 respectively. Both autoantigens are expressed in hepatocytes at higher levels than in any other cell type. Therefore, compared to AIH-1, the autoantigens targeted in AIH-2 are predominantly tissue-specific. Distinct clinical features are specific to AIH-2 compared to AIH-1, including diagnosis in younger patients (mean age 6.6 years), onset as fulminant hepatitis in very young patients (3 years of age or less), higher frequency in children than in adults and is frequently associated with extrahepatic T cell-mediated autoimmune diseases. AIH-2 is also often diagnosed in patients with primary immunodeficiency. AIH-2 is associated with specific HLA class II susceptibility alleles; DQB1*0201 is considered the main determinant of susceptibility while DRB1*07/DRB1*03 is associated with the type of autoantibody present. HLA DQB1*0201 is in strong linkage disequilibrium with both HLA DRB1*03 and DRB1*07. Interestingly, as in humans, MHC and non-MHC genes strongly influence the development of the disease in an animal model of AIH-2. Altogether, these findings suggest that AIH-2 incidence is likely dependent on specific genetic susceptibility factors combined with distinct environmental triggers.

PMID:36248826 | PMC:PMC9556705 | DOI:10.3389/fimmu.2022.1025343

Allergy Asthma Clin Immunol. 2022 Oct 16;18(1):91. doi: 10.1186/s13223-022-00730-x.

ABSTRACT

BACKGROUND: Since the first reported case of COVID-19, infections due to the virus have ranged from mild to severe. Patients with inborn errors of immunity are thought to be at increased risk for infections such as COVID-19 due to the nature of their disease and being immunocompromised. Similarly, pregnant women by nature of physiological changes in immunity are susceptible to infections and consequently are felt to be at greater risk of contracting COVID-19 with potential grave consequences for not only the mother but also the fetus. Early treatment with novel therapeutics against the SARS-CoV-2 virus to prevent progression and these complications is paramount.

CASE PRESENTATION: A 31-year-old woman with a 22-year history of common variable immunodeficiency on subcutaneous immunoglobulin replacement therapy and 24 weeks pregnant with her third child presented to the Emergency Department with two-day history of pharyngitis that progressed to include nasal and chest congestion, non-productive cough and shortness of breath. Her vitals indicated temperature of 35 degrees Celsius, heart rate of 109 beats per minute, blood pressure 142/92 mmHg, respiratory rate 22/min and an oxygen saturation of 99% on room air. A workup was done and she was found to be positive for SARS-CoV-2 virus confirmed by PCR. She had a close contact, her husband, who had tested positive a few days prior. She had been previously vaccinated with three doses of the Moderna COVID-19 (Spikevax ®) vaccine. As she met the criteria for monoclonal antibody treatment, she received Sotrovimab on the same day of testing positive and tolerated it well with no side-effects. Her symptoms resolved within two to three days.

CONCLUSION: Our case, is the first to our knowledge, of a pregnant patient with common variable immunodeficiency diagnosed with COVID-19 and symptomatic successfully receiving treatment with Sotrovimab. Her rapid resolution of symptoms makes the use of monoclonal antibodies such as Sotrovimab a safe and useful option in this unique population.

PMID:36244996 | DOI:10.1186/s13223-022-00730-x

Iran J Allergy Asthma Immunol. 2022 Aug 12;21(4):488-493. doi: 10.18502/ijaai.v21i4.10297.

ABSTRACT

Type 2 Griscelli syndrome (Type2 GS) is a primary inborn error of the immune system, classified in the immune dysregulation group.1,2 There are three different types of the disease, with different genetic causes responsible for the autosomal recessive inheritance pattern. Although hypopigmentation is common in all variants, neurological involvement or immunodeficiency with varying severity is seen in different types. Molecular motor protein myosin 5 an (MYo5A) [Type1GS], guanosine Triphosphate (GTP) binding protein (RAB27A) [Type2GS], and mutation in human melanophilin (MLPH) [Type 3GS] which is limited to hypopigmentation are reported as the known genetic defects in GS.3 Severe, ineffective, and uncontrolled inflammatory reactions are referred to as the pathogenesis of Hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening condition that can be defined as either primary or secondary. Secondary causes happen in the context of autoimmunity, malignancy, spontaneous, or infections.4 Prenatal infections play an important role in causing long-term complications in the fetus. Some of them include toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and other organisms including syphilis, parvovirus, and Varicella zoster, known as TORCH syndrome (5).TORCH has been well described for a long time but there are limited reports of developing HLH in the context of prenatal infections. We described a type 2GS syndrome with neonatal-onset HLH triggered by a prenatal infection.

PMID:36243938 | DOI:10.18502/ijaai.v21i4.10297

Iran J Allergy Asthma Immunol. 2022 Aug 12;21(4):374-387. doi: 10.18502/ijaai.v21i4.10285.

ABSTRACT

The majority of primary immunodeficiencies (PIDs) are antibody deficiencies (PADs), and not all of them are rare diseases; As an example, Caucasian individuals suffer from selective IgA deficiency at a frequency of 1:500. In addition to infections, symptomatic patients with PAD are more likely to develop neoplastic, autoimmune, and allergic diseases. In the event that PAD is neglected or delayed for more than ten years, complications develop, eventually resulting in death. No studies have been conducted to devise and report detailed ready-to-use protocols for managing PAD to date. This study aimed to propose protocols and guidelines for the adult PAD patients’ standard care. Preparing the protocol, we considered the frequency and type of laboratory tests, imaging, endoscopic examinations, specialist consultations, and standardized recommendations for further care in the place of residence. As a result of the proposed monitoring scheme, patients can be provided with complete care in terms of their underlying conditions and comorbidities, as well as early detection of complications. This protocol will serve as a guide for physicians dealing with these patients and enable comparisons of patient groups across a variety of treatment centers, even far away from each other. A national consultant in the field of clinical immunology verified the protocol mainly developed by Polish experts from reference immunology centres for adults.

PMID:36243926 | DOI:10.18502/ijaai.v21i4.10285

J Allergy Clin Immunol. 2022 Oct 12:S0091-6749(22)01343-4. doi: 10.1016/j.jaci.2022.10.005. Online ahead of print.

ABSTRACT

BACKGROUND: Identification of patients with underlying inborn errors of immunity and inherent susceptibility to infection remains challenging. The ensuing protracted diagnostic odyssey for such patients often results in greater morbidity and suboptimal outcomes underscoring a need to develop systematic methods for improving diagnostic rates.

OBJECTIVE: The principal aim of this study is to build and validate a generalizable analytical pipeline for population-wide detection of infection susceptibility and risk of primary immunodeficiency.

METHODS: This prospective, longitudinal cohort study coupled weighted rules with a machine learning classifier for risk stratification. Claims data were analyzed from a diverse population (n = 427,110) iteratively over 30 months. Cohort outcomes were enumerated for new diagnoses, hospitalizations and acute care visits. We followed Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis standards.

RESULTS: Cohort members initially identified as high-risk were proportionally more likely to receive a diagnosis of PI compared to low-medium risk or those without claims of interest respectively (9% vs. 1.5% vs. 0.2%; p < 0.001 Chi-Square). Subsequent machine learning stratification enabled an annualized individual snapshot of complexity for triaging referrals. Our top-performing machine learning model for visit-level prediction utilized a single dense layer neural network architecture (AUROC = 0.98, F1 Score = 0.98).

CONCLUSIONS: Here we show that a 2-step analytical pipeline can facilitate identification of individuals with primary immunodeficiency and accurately quantify clinical risk.

CLINICAL IMPLICATIONS: This transparent, generalizable methodology links predictions with clinical outcomes which is expected to facilitate early diagnosis of patients with primary immunodeficiency.

PMID:36243223 | DOI:10.1016/j.jaci.2022.10.005

Front Immunol. 2022 Sep 27;13:959733. doi: 10.3389/fimmu.2022.959733. eCollection 2022.

ABSTRACT

INTRODUCTION: The transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals.

OBJECTIVE: We aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology.

METHODS: After informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells.

RESULTS: We describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis.

DISCUSSION: NFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

PMID:36238298 | PMC:PMC9552184 | DOI:10.3389/fimmu.2022.959733

J Clin Med. 2022 Sep 27;11(19):5705. doi: 10.3390/jcm11195705.

ABSTRACT

BACKGROUND: Selective IgA deficiency (SIgAD) is the most common inborn error of immunity. The exact prevalence and pathogenesis of allergy in SIgAD have not yet been defined. We aimed to describe the prevalence and the characteristics of allergy in pediatric SIgAD subjects, evaluate the association between allergy and other comorbidities, and define the immune phenotype of allergic and non-allergic patients.

METHODS: Clinical and immunological data from 67 SIgAD patients were collected over a 13-year period at a single center. Patients’ characteristics were analyzed according to the presence of allergy.

RESULTS: Allergy was diagnosed in 34% of SIgAD patients, with a median age at allergy diagnosis of 8 years. Allergy was the second-most-common clinical manifestation, following recurrent respiratory infections. Among the allergic group, 74% had rhinitis, 30% asthma, 30% atopic dermatitis, and 22% food allergy; one out of three had more than one allergic manifestation. SIgAD patients showed more frequent transitory lymphopenia and a lower count of CD19+ at diagnosis than at last FU. However, compared to non-allergic subjects, allergic patients did not differ in their immune phenotype, number and severity of infections, or increased autoimmunity.

CONCLUSIONS: In our longitudinal study, compared to non-allergic SIgAD patients, those with allergies did not present a more severe immune defect or complex clinical phenotype. However, evaluation and early identification of allergy in the context of SIgAD assessment, both at diagnosis and during FU, and definition of a proper management are important to prevent complications and improve the patient’s quality of life.

PMID:36233573 | DOI:10.3390/jcm11195705

Int J Mol Sci. 2022 Sep 22;23(19):11141. doi: 10.3390/ijms231911141.

ABSTRACT

Macrophages have emerged as important therapeutic targets in many human diseases. The aim of this study was to analyze the effect of broccoli membrane vesicles and sulphoraphane (SFN), either free or encapsulated, on the activity of human monocyte-derived M1 and M2 macrophage primary culture. Our results show that exposure for 24 h to SFN 25 µM, free and encapsulated, induced a potent reduction on the activity of human M1 and M2 macrophages, downregulating proinflammatory and anti-inflammatory cytokines and phagocytic capability on C. albicans. The broccoli membrane vesicles do not represent inert nanocarriers, as they have low amounts of bioactive compounds, being able to modulate the cytokine production, depending on the inflammatory state of the cells. They could induce opposite effects to that of higher doses of SFN, reflecting its hormetic effect. These data reinforce the potential use of broccoli compounds as therapeutic agents not only for inflammatory diseases, but they also open new clinical possibilities for applications in other diseases related to immunodeficiency, autoimmunity, or in cancer therapy. Considering the variability of their biological effects in different scenarios, a proper therapeutic strategy with Brassica bioactive compounds should be designed for each pathology.

PMID:36232440 | DOI:10.3390/ijms231911141

J Clin Immunol. 2022 Oct 13. doi: 10.1007/s10875-022-01381-8. Online ahead of print.

ABSTRACT

Little is known about major histocompatibility complex type I deficiency, a rare form of primary immunodeficiency. This report describes the presentation of a three-year-old Ethiopian boy with recurrent sinopulmonary infections and genetic analysis showing him having autosomal recessive major histocompatibility complex type I deficiency-the first such report in a child of black African descent-and follows it with a summary of existing literature on the epidemiology, presentation, and diagnosis as well as principles of management of this disorder.

PMID:36229627 | DOI:10.1007/s10875-022-01381-8

J Allergy Clin Immunol. 2022 Oct 10:S0091-6749(22)01182-4. doi: 10.1016/j.jaci.2022.09.002. Online ahead of print.

ABSTRACT

BACKGROUND: In 2014, germline STAT3 gain of function (GOF) mutations were first described to cause a novel multi-system disease of early onset lymphoproliferation and autoimmunity.

OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.

METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.

RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double negative (CD4^–CD8^–) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplant with 62% survival rate.

CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias and multisystem autoimmunity. Patient care tends to be siloed without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

PMID:36228738 | DOI:10.1016/j.jaci.2022.09.002