Research

Expert Rev Clin Immunol. 2022 Mar 16. doi: 10.1080/1744666X.2022.2054414. Online ahead of print.

ABSTRACT

INTRODUCTION: As the prevalence of food allergies (FA) increases worldwide, our understanding of its pathophysiology and risk factors is markedly expanding. In the past decades, an increasing number of genes have been linked to FA. Identification of such genes may help in predicting the genetic risk for FA development, age of onset, clinical manifestation, causative allergen(s), and possibly the optimal treatment strategies. Furthermore, identification of these genetic factors can help to understand the complex interactions between genes and the environment in predisposition to FA.

AREAS COVERED: We outline the recent important progress in determining genetic variants and disease-associated genes in IgE-mediated FA. We focused on the monogenic inborn errors of immunity (IEI) where FA is one of the clinical manifestations, emphasizing the genes and gene variants which were linked to FA with some of the most robust evidence.

EXPERT OPINION: Genetics play a significant role, either directly or along with environmental factors, in the development of FA. Since FA is a multifactorial disease, it is expected that multiple genes and genetic loci contribute to the risk for its development. Identification of the involved genes should contribute to the area of FA regarding pathogenesis, prediction, recognition, prognosis, prevention, and possibly therapeutic interventions.

PMID:35293838 | DOI:10.1080/1744666X.2022.2054414

Immunopharmacol Immunotoxicol. 2022 Apr;44(2):147-156. doi: 10.1080/08923973.2021.2023173. Epub 2022 Jan 4.

ABSTRACT

Primary immunodeficiency diseases (PIDs) consist of a heterogeneous group of genetically disorders that affect distinct components of the immune system. They manifest as increased susceptibility to life-threatening infections, as well as autoimmunity and inflammatory disease. Among them, patients with diseases of immune dysregulation and autoinflammatory disorders are more complicated with autoimmunity. On the other hand, tumor necrosis factor alpha (TNF-α) is one of the major players in the pathogenesis of autoimmunity and inflammation in PID patients. Monoclonal antibodies (mAbs) targeting TNF-α would be a potential approach as a therapeutic tool for these diseases. In the current review, we aimed to highlight the characteristics of TNF-α and its important role in the pathogenesis of related complication in PID diseases. Critical evaluation of the mAbs targeting TNF-α (e.g. infliximab, etanercept, and adalimumab) in various immune-mediated complications in PID diseases will be provided, and finally, their clinical efficacy and safety will be reported.

PMID:35296212 | DOI:10.1080/08923973.2021.2023173

Platelets. 2022 Mar 16:1-4. doi: 10.1080/09537104.2022.2053090. Online ahead of print.

ABSTRACT

Autoimmune disorders are common in patients with primary immunodeficiency diseases (PIDs). However, the prevalence of autoimmunity is low in patients with X-linked agammaglobulinemia (XLA), mostly due to the absence of antibodies. Chronic or persistent immune thrombocytopenia (ITP), which is usually considered an antibody-mediated disease, is uncommon in patients with XLA. In this study, we detailly described a surprising autoimmune phenomenon, chronic ITP, in a small boy diagnosed with XLA. This is an interesting phenotype found in XLA, and it is helpful to understand the immune pathogenesis of autoimmunity in patients with XLA.

PMID:35296220 | DOI:10.1080/09537104.2022.2053090

Clin Rev Allergy Immunol. 2022 Mar 15. doi: 10.1007/s12016-022-08933-1. Online ahead of print.

ABSTRACT

As the field of inborn errors of immunity expands, providers continually update and fine-tune their diagnostic approach and selection of testing modalities to increase diagnostic accuracy. Here, we first describe a mechanistic consideration of laboratory testing, highlighting both benefits and drawbacks of currently clinically available testing modalities. Next, we provide methods in evaluation of patients presenting with concern for inborn errors of immunity as defined by the International Union of Immunological Societies 2019 phenotypic categories: primary antibody deficiencies, cellular and humoral immune deficiency, disorders of the innate immune system, and syndrome-associated and primary immune regulation disorders (PIRDs). Using the suggested approach in this paper as a roadmap highlights the importance of thorough history taking and physical examination as the foundation to guide further diagnostic tests. This is followed by enumeration and functional testing. Finally, to determine the underlying molecular etiology-specific genetic panels, chromosomal microarrays, and broad genetic testing (whole exome sequencing or whole genome sequencing) are available.

PMID:35290615 | DOI:10.1007/s12016-022-08933-1

Iran J Med Sci. 2022 Mar;47(2):162-166. doi: 10.30476/IJMS.2022.92862.2415.

ABSTRACT

Both adaptive and innate immune responses are essential for an effective defense against the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection. We aimed to investigate the effect of the coronavirus disease 2019 (COVID-19) pandemic on patients with primary immunodeficiency (PID). This study was performed on patients who were diagnosed with PID by immunologist specialists and referred to Imam Reza Clinic of Asthma and Allergy, affiliated with Shiraz University of Medical Sciences, (Shiraz, Iran) for regular check-ups. The patients were enrolled in this cohort study and followed for any sign of COVID-19 from March 2020 to May 2021. COVID-19 infection was confirmed using a real-time polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Among the 90 PID patients under study, nine patients (10%) were diagnosed positive for COVID-19 infection. Five out of these nine patients belonged to the combined immunodeficiency (CID) category, while four patients were categorized as having primary antibody deficiencies (PADs). Eight patients with COVID-19 were required to be admitted to the hospital, and three patients died after hospitalization due to COVID-19 infection. It seems that patients with CID are at a higher risk of mortality, due to COVID-19 infection, that other types of PID.

PMID:35291437 | PMC:PMC8919309 | DOI:10.30476/IJMS.2022.92862.2415

J Clin Immunol. 2022 Mar 15. doi: 10.1007/s10875-022-01237-1. Online ahead of print.

ABSTRACT

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by mutations in the Bruton tyrosine kinase (BTK) gene leading to B lymphocyte deficiency and susceptibility to infection. A potential benefit of earlier diagnosis and treatment initiation on morbidity and mortality in XLA is incompletely understood. In the USIDNET Registry, we describe infection frequency and infection-related mortality in patients with XLA and their relationship to age of diagnosis and treatment initiation. Among the 231 XLA patients enrolled in the Registry, respiratory infections (N = 203, 88%) were the most commonly reported. Among those deceased (N = 20) where cause of death was known (N = 17), mortality was attributed to infection in most (N = 12, 71%). Chronic lung disease, often a consequence of repeated lower respiratory tract infection (LRTI), was also a frequent complication associated with mortality (N = 9, 53%). Age of diagnosis in years was lower for those without LRTI compared to those with (median 1.5 [IQR 0.5-3.3] vs. median 3.0 [IQR 1.0-5.0], p = 0.0026) and among living patients compared to deceased (median 1.8 [IQR 0.5-5.0] vs. median 2.7 [IQR 1.6-6.0], p = 0.04). Age at treatment initiation in years was lower among those without LRTIs compared to those with (median 1.0 [IQR 0.4-2.4] vs. median 2.8 [IQR 1.0-5.4], p = 0.0006). For every year increase in age at start of therapy, the odds of experiencing a LRTI was 1.216 (OR 1.216, 95% CI 1.048-1.411, p = 0.01). Given the expected finding of reduced LRTIs and mortality among those with earlier age at diagnosis, our study findings support inclusion of XLA in newborn screening programs.

PMID:35288819 | DOI:10.1007/s10875-022-01237-1

J Clin Immunol. 2022 Mar 14. doi: 10.1007/s10875-022-01240-6. Online ahead of print.

NO ABSTRACT

PMID:35286514 | DOI:10.1007/s10875-022-01240-6

Front Oncol. 2022 Feb 25;12:829777. doi: 10.3389/fonc.2022.829777. eCollection 2022.

ABSTRACT

BACKGROUND: Breast cancer (BRCA) has become the most frequently appearing, lethal, and aggressive cancer with increasing morbidity and mortality. Previously, it was discovered that the HAUS5 protein is involved in centrosome integrity, spindle assembly, and the completion of the cytoplasmic division process during mitosis. By encouraging chromosome misdivision and aneuploidy, HAUS5 has the potential to cause cancer. The significance of HAUS5 in BRCA and the relationship between its expression and clinical outcomes or immune infiltration remains unclear.

METHODS: Pan-cancer was analyzed by TIMER2 web and the expression differential of HAUS5 was discovered. The prognostic value of HAUS5 for BRCA was evaluated with KM plotter and confirmed with Gene Expression Omnibus (GEO) dataset. Following that, we looked at the relationship between the high and low expression groups of HAUS5 and breast cancer clinical indications. Signaling pathways linked to HAUS5 expression were discovered using Gene Set Enrichment Analysis (GSEA). The relative immune cell infiltrations of each sample were assessed using the CIBERSORT algorithm and ESTIMATE method. We evaluated the Tumor Mutation Burden (TMB) value between the two sets of samples with high and low HAUS5 expression, as well as the differences in gene mutations between the two groups. The proliferation changes of BRCA cells after knockdown of HAUS5 were evaluated by fluorescence cell counting and colony formation assay.

RESULT: HAUS5 is strongly expressed in most malignancies, and distinct associations exist between HAUS5 and prognosis in BRCA patients. Upregulated HAUS5 was associated with poor clinicopathological characteristics such as tumor T stage, ER, PR, and HER2 status. mitotic prometaphase, primary immunodeficiency, DNA replication, cell cycle related signaling pathways were all enriched in the presence of elevated HAUS5 expression, according to GSEA analysis. The BRCA microenvironment’s core gene, HAUS5, was shown to be related with invading immune cell subtypes and tumor cell stemness. TMB in the HAUS5-low expression group was significantly higher than that in the high expression group. The mutation frequency of 15 genes was substantially different in the high expression group compared to the low expression group. BRCA cells’ capacity to proliferate was decreased when HAUS5 was knocked down.

CONCLUSION: These findings show that HAUS5 is a positive regulator of BRCA progression that contributes to BRCA cells proliferation. As a result, HAUS5 might be a novel prognostic indicator and therapeutic target for BRCA patients.

PMID:35280773 | PMC:PMC8913513 | DOI:10.3389/fonc.2022.829777

Front Med (Lausanne). 2022 Feb 23;9:814300. doi: 10.3389/fmed.2022.814300. eCollection 2022.

ABSTRACT

Combined variable immunodeficiency (CVID) is a primary immunodeficiency, characterized by impairment in immune system function. These patients are susceptible to opportunistic infections, which may mimic COVID-19 manifestations. Also, misdiagnosis or delayed diagnosis of opportunistic infections can lead to perilous consequences. We report a 28-year-old woman with a history of combined variable immunodeficiency disorder (CVID) and ulcerative colitis (UC) complained of fever, cough, and dyspnea. According to the clinical and radiological manifestations and the COVID-19 epidemic, she was admitted with a primary diagnosis of COVID-19 pneumonia. After a week, the patient did not respond to treatment, so she underwent bronchoscopy. Using polymerase chain reaction (PCR) methodology, we detected DNA of Pneumocystis jirovecii, the causative agent of a life-threatening pneumonia (PCP), in respiratory specimens. The patient was hypersensitive to common PCP treatments, so she was treated with high-dose clindamycin. However, the patient’s clinical condition aggravated. Besides, we found evidence of pneumothorax, pneumomediastinum, and pneumopericardium in chest CT scan. We inserted a catheter for the patient to evacuate the air inside the mediastinum. Also, we added caspofungin to the treatment. The patient eventually recovered and was discharged from the hospital about a week later. Thus, during the COVID-19 epidemic, in febrile patients with respiratory symptoms, physicians should not think only of COVID-19. They must consider opportunistic infections such as PCP, especially in immunocompromised patients.

PMID:35280884 | PMC:PMC8904891 | DOI:10.3389/fmed.2022.814300

Front Immunol. 2022 Feb 23;13:813491. doi: 10.3389/fimmu.2022.813491. eCollection 2022.

ABSTRACT

BACKGROUND: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a distinct clinic-radio-pathological interstitial lung disease (ILD) that develops in 9% to 30% of patients with common variable immunodeficiency (CVID). Often related to extrapulmonary dysimmune disorders, it is associated with long-term lung damage and poorer clinical outcomes. The aim of this study was to explore the potential use of the integration between clinical parameters, laboratory variables, and developed CT scan scoring systems to improve the diagnostic accuracy of non-invasive tools.

METHODS: A retrospective cross-sectional study of 50 CVID patients was conducted in a referral unit of primary immune deficiencies. Clinical variables including demographics and comorbidities; analytical parameters including immunoglobulin levels, lipid metabolism, and lymphocyte subpopulations; and radiological and lung function test parameters were collected. Baumann’s GLILD score system was externally validated by two observers in high-resolution CT (HRCT) scans. We developed an exploratory predictive model by elastic net and Bayesian regression, assessed its discriminative capacity, and internally validated it using bootstrap resampling.

RESULTS: Lymphadenopathies (adjusted OR 9.42), splenomegaly (adjusted OR 6.25), Baumann’s GLILD score (adjusted OR 1.56), and CD8+ cell count (adjusted OR 0.9) were included in the model. The larger range of values of the validated Baumann’s GLILD HRCT scoring system gives it greater predictability. Cohen’s κ statistic was 0.832 (95% CI 0.70-0.90), showing high concordance between both observers. The combined model showed a very good discrimination capacity with an internally validated area under the curve (AUC) of 0.969.

CONCLUSION: Models integrating clinics, laboratory, and CT scan scoring methods may improve the accuracy of non-invasive diagnosis of GLILD and might even preclude aggressive diagnostic tools such as lung biopsy in selected patients.

PMID:35281075 | PMC:PMC8906473 | DOI:10.3389/fimmu.2022.813491