Manish Butte

Front Immunol. 2021 Oct 14;12:749794. doi: 10.3389/fimmu.2021.749794. eCollection 2021.

ABSTRACT

Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins-a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a ‘hyperinflammatory’ phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases.

PMID:34721419 | PMC:PMC8552041 | DOI:10.3389/fimmu.2021.749794

Clin Med Insights Case Rep. 2021 Oct 26;14:11795476211052415. doi: 10.1177/11795476211052415. eCollection 2021.

ABSTRACT

Cat-scratch disease can be transmitted from cats and dogs in winter. It is usually self-limited and caused by Bartonella henselae. It may cause serious symptoms, including neurological findings, especially in immune-deficient patients. A female patient was referred to our outpatient clinic at the age of 3 years and 10 months with a preliminary diagnosis of neurodegenerative metabolic disease. Her complaints began after a stray cat scratched her. We found out that the hospital to which she was admitted provided only local wound care due to her history of contact with a cat and that she was vaccinated against rabies. Her body temperature increased, her neck lymph nodes became swollen, and she developed otitis and mastoiditis after 1 month. Additionally, we discovered that she had deteriorated in her walking ability after 6 weeks and developed hand tremors after 10 weeks. It was discovered that previous centers to which the patient applied did not question cat contact. All metabolic tests performed for the differential diagnosis of last admission findings were considered nonspecific. Considering cat-scratch disease due to her clinical history, she was referred to the pediatric infection unit for a Bartonella henselae test, and the test result was 1/256 positive. Failure to follow basic medical rules might be costly in diagnosis and treatment. Cat scratch disease is a zoonosis and a major public health problem. In differential diagnosis, these medical procedures should always be considered before rare metabolic diseases.

PMID:34720603 | PMC:PMC8552389 | DOI:10.1177/11795476211052415

J Allergy Clin Immunol Pract. 2021 Oct 27:S2213-2198(21)01185-5. doi: 10.1016/j.jaip.2021.10.033. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiency disorders (PIDD) describe a myriad of diseases caused by inherited defects within the immune system. As the number of identified genetic defects associated with PIDD increases, understanding the incidence and outcomes of PIDD patients becomes imperative.

OBJECTIVE: To characterize the frequency of new diagnoses, patterns of healthcare utilization, rates of hematopoietic stem cell transplantation (HSCT), and mortality in pediatric patients with PIDD.

METHODS: A retrospective cohort analysis of the Pediatric Health Information System (PHIS) database from 2004-2018 for pediatric inpatients with an ICD9/ICD10 code associated with PIDD.

RESULTS: A total of 17,234 patients with a PIDD were hospitalized from 2004-2018. There were 2.8 new PIDD diagnoses and 6.3 PIDD hospitalizations per 1,000 discharges; these metrics were unchanged during the study period. The number of new diagnoses for B cell and antibody defects significantly increased over time. The number of new PIDD diagnoses significantly increased in adolescents/adults and decreased in infants. T cell disorders had the highest number of ICU admissions. There were 747 PIDD patients who underwent HSCT; complications of HSCT significantly decreased over time. Mortality rates significantly decreased in all PIDD patients and in patients receiving HSCT.

CONCLUSIONS: The total hospitalizations and incidence of PIDD within the hospitalized pediatric population were unchanged. There were significant changes in the class of PIDD diagnosed, the age at diagnosis, and healthcare utilization metrics. Mortality significantly decreased over time within the PIDD cohort.

PMID:34718217 | DOI:10.1016/j.jaip.2021.10.033

J Allergy Clin Immunol. 2021 Oct 27:S0091-6749(21)01629-8. doi: 10.1016/j.jaci.2021.10.017. Online ahead of print.

ABSTRACT

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome.

OBJECTIVE: To perform a comprehensive multicenter analysis of genotype-specific HSCT outcome including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome.

METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID, transplanted in 2006-2014 and registered in the SCETIDE registry. In a representative subgroup of n=152 patients data on IR and long-term clinical outcome were analyzed.

RESULTS: 2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT (p < 0.001). The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (p < 0.001). Genetic subgroups did not differ in 2-year OS (p=0.1) and EFS (p=0.073). In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency. IL2Rγ-JAK3-IL7R deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/μL at +1-year were identified as independent predictors of favorable clinical and immunological outcome.

CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long term outcome, treatment strategies should aim for optimal naïve CD4 T lymphocyte regeneration.

PMID:34718043 | DOI:10.1016/j.jaci.2021.10.017

J Clin Immunol. 2021 Oct 30. doi: 10.1007/s10875-021-01156-7. Online ahead of print.

ABSTRACT

DNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency.

PMID:34716846 | DOI:10.1007/s10875-021-01156-7

J Clin Immunol. 2021 Oct 29. doi: 10.1007/s10875-021-01154-9. Online ahead of print.

ABSTRACT

PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized chiefly by the hypoplasia of the thymus resulting in T cell lymphopenia, increased susceptibility to infections, and higher risk of autoimmune diseases. The irregular thymic niche of T cell development may contribute to autoimmune and atopic complications, whereas the compensatory mechanism of homeostatic T cell proliferation and continuous immune stimulation may result in T cell senescence and exhaustion, further aggravating the immune system dysregulation.

METHODS: We used flow cytometry to investigate T cell maturation, delineation, proliferation, activation, and expression of senescence and exhaustion-associated markers (PD1, KLRG1, CD57) in 17 pediatric and adolescent patients with 22q11.2DS and age-matched healthy donors.

RESULTS: 22q11.2DS patients aged 0-5 years had fewer naïve but more effector memory T cells with a tendency to approach normal values with increasing age. Young patients in particular had a higher percentage of proliferating T cells and increased expression of PD1, KLRG1, and CD57, as well as cells co-expressing several exhaustion-associated molecules (PD1, KLRG1, Tbet, Eomes, Helios). Additionally, high-risk 22q11.2DS patients with very low numbers of CD4 T cells had significantly higher percentage of Th1 and Th17 T cells, driven in part by higher proportion of mature T cell forms.

CONCLUSION: The low thymic output and accelerated T cell differentiation remain the principal features of 22q11.2DS patient immunity, especially in young patients of < 5 years. Later in life, homeostatic proliferation drives expression of T cell exhaustion and senescence-associated markers, suggesting functional aberrations in addition to numeric T cell deficiency.

PMID:34716533 | DOI:10.1007/s10875-021-01154-9

Int J Surg Pathol. 2021 Oct 29:10668969211054102. doi: 10.1177/10668969211054102. Online ahead of print.

ABSTRACT

Short telomere syndrome (STS) encompasses a broad family of genetically inherited conditions caused by various mutations in telomerase and other telomere maintenance genes, resulting in premature telomere shortening. STS involves a variety of clinical manifestations, including dyskeratosis congenita, premature achromotrichia, bone marrow failure, immunodeficiency, pulmonary fibrosis and liver disease. Liver histopathologic features in STS patients have not been well characterized. We report a 46-year-old male patient who presented for dyspnea. The patient had a complicated medical history significant for immune thrombocytopenic purpura and splenectomy, recurrent respiratory tract infections, pneumonia, primary immunodeficiency, and severe hepatopulmonary syndrome. He and his brother both developed gray hair by their late 20s. He had a long history of intermittently elevated liver enzymes starting at age 33. These clinical manifestations prompted an evaluation for a possible telomere biology disorder, which revealed the telomere length was critically short and fell at or below the first percentile for age, supporting the diagnosis. The liver biopsy showed marked portal inflammation with interface hepatitis, ductular reaction and frequent foci of lobular inflammation with focal hepatocyte dropout. Hepatocytes around the portal tracts demonstrated ballooning degeneration and occasional Mallory-Denk bodies. A trichrome stain highlighted bridging fibrosis. A literature review shows liver histology is available in only a small number of STS patients, demonstrating a variety of morphologic features. Our case and others suggest liver disease associated with STS exhibits a spectrum of histopathology. Being aware of these features is important for establishing the correct diagnosis of STS which is under recognized.

PMID:34714693 | DOI:10.1177/10668969211054102

Clin Genet. 2021 Oct 27. doi: 10.1111/cge.14081. Online ahead of print.

ABSTRACT

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55,000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings. This article is protected by copyright. All rights reserved.

PMID:34708404 | DOI:10.1111/cge.14081

Bull Exp Biol Med. 2021 Oct 27. doi: 10.1007/s10517-021-05313-1. Online ahead of print.

ABSTRACT

The experimental model of synchronous multiple primary malignant tumors (MPMT) was created. B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline) and sarcoma 45 (0.5 million tumor cells in 0.5 ml saline) were simultaneously subcutaneously inoculated to male BALB/c nude mice. In the model of synchronous MPMT, the tumors appeared faster by 2.4 times and had greater volumes: melanoma by 2.2 times and sarcoma by 3.2 times; melanoma metastasized into sarcoma in 71.4% cases; the survival of mice with MPMT was lower. The altered dynamics of malignant growth in the MPMT model is based on the mutual influence of tumors, which results in the exchange of “structural information”.

PMID:34705181 | DOI:10.1007/s10517-021-05313-1

Ann Biol Clin (Paris). 2021 Oct 26. doi: 10.1684/abc.2021.1670. Online ahead of print.

ABSTRACT

Common variable immunodeficiency (CVID) is one of the most prevalent primary immunodeficiencies. It is characterized by hypogammaglobulinaemia, increased susceptibility to infections and impaired vaccine responses. CVID has an important, clinical, immunological and genetic heterogeneity. A minority of patients present with monogenic forms in CVID, unlike other primary immunodeficiencies. With the development of new technologies in genetics, including next generation sequencing, the number of identified genes in CVID is increasing. Therefore, CVID is now considered as an umbrella disease, gathering distinct pathological entities. It is currently recognized that CVID is a complex polygenic rather than a monogenic syndrome. A multi-omic approach combining genomics, epigenetics and proteomics will shed light on CVID complex pathophysiology, which still enigmatic. This integrative approach will also offer more targeted therapies, and therefore a personalized medicine. This review aims to discuss current knowledge concerning the genetic and molecular bases of CVID as well as their application in clinical practice.

PMID:34704938 | DOI:10.1684/abc.2021.1670