Research

J Immunother Cancer. 2022 Jan;10(1):e003459. doi: 10.1136/jitc-2021-003459.

ABSTRACT

BACKGROUND: While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive.

METHODS: Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2’3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances T_H9 cell antitumor activity against mouse melanoma upon adoptive transfer.

RESULTS: We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T_H1 and T_H9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of T_H1 cell differentiation. However, STING activation favors T_H9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on T_H1 and T_H9-derived cytokines, and STING activation enhances the antitumor activity of T_H9 cells upon adoptive transfer.

CONCLUSION: Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

PMID:35091453 | DOI:10.1136/jitc-2021-003459

J Allergy Clin Immunol Pract. 2022 Jan 24:S2213-2198(22)00023-X. doi: 10.1016/j.jaip.2022.01.007. Online ahead of print.

ABSTRACT

Treatment with immune modifying biologicals has positively impacted disease control and quality of life in many patients with immune-mediated disorders. However, the higher susceptibility to common and opportunistic pathogens is of concern. Thus, immunization strategies to control vaccine preventable diseases represent a critical issue in this population. However, limited data exist on the safety, immunogenicity and efficacy of available vaccines in patients on biologicals, particularly in children. Here, according to published literature and real life experience and practice, we report the interim indications of the Italian Society of Pediatric Allergology and Immunology (SIAIP) Vaccine Committee and of the Italian Primary Immunodeficiency Network (IPINET) Centers, on immunization of children and adolescents receiving biologicals. Our aim is to provide a practical guidance for the clinician to ensure optimal protection for patients and the community.

PMID:35085809 | DOI:10.1016/j.jaip.2022.01.007

Front Immunol. 2022 Jan 10;12:805766. doi: 10.3389/fimmu.2021.805766. eCollection 2021.

ABSTRACT

The Primary Immunodeficiency Database in Japan (PIDJ) is a registry of primary immunodeficiency diseases (PIDs) that was established in 2007. The database is a joint research project with research groups associated with the Ministry of Health, Labor and Welfare; the RIKEN Research Center for Allergy and Immunology (RCAI); and the Kazusa DNA Research Institute (KDRI). The PIDJ contains patient details, including the age, sex, clinical and laboratory findings, types of infections, genetic analysis results, and treatments administered. In addition, web-based case consultation is also provided. The PIDJ serves as a database for patients with PIDs and as a patient consultation service connecting general physicians with PID specialists and specialized hospitals. Thus, the database contributes to investigations related to disease pathogenesis and the early diagnosis and treatment of patients with PIDs. In the 9 years since the launch of PIDJ, 4,481 patients have been enrolled, of whom 64% have been subjected to genetic analysis. In 2017, the Japanese Society for Immunodeficiency and Autoinflammatory Diseases (JSIAD) was established to advance the diagnosis, treatment, and research in the field of PIDs and autoinflammatory diseases (AIDs). JSIAD promotes the analysis of the pathogenesis of PIDs and AIDs, enabling improved patient care and networking via the expansion of the database and construction of a biobank obtained from the PIDJ. The PIDJ was upgraded to “PIDJ ver.2” in 2019 by JSIAD. Currently, PIDJ ver.2 is used as a platform for epidemiological studies, genetic analysis, and pathogenesis evaluation for PIDs and AIDs.

PMID:35082792 | PMC:PMC8786595 | DOI:10.3389/fimmu.2021.805766

J Clin Immunol. 2022 Jan 27. doi: 10.1007/s10875-022-01211-x. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) is an inborn error of immunity (IEI) characterized by various clinical manifestations such as hypogammaglobulinemia, recurrent infections, and autoimmune diseases. Among different clinical manifestations, skin manifestations have been less reported in these patients.

METHODS: In this study, we investigated the prevalence of dermatologic features in 387 CVID patients. Demographic information, clinical manifestations, laboratory data, and genetic findings were collected from medical records. All data were analyzed based on the presence or absence of skin disorders in CVID patients.

RESULTS: We observed at least one skin manifestation in about 40% of these patients. Among these complications, skin infection (n = 64, 42.1%) was the most frequent presentation, followed by non-infectious skin lesions (n = 54, 35.6%). Among skin infections, abscesses (n = 34, 22.4%) were the most common complication. Skin infections such as cellulitis, impetigo, measles, and warts were also documented. Eczema (n = 34, 22.4%) was the most common complication in atopic lesions, and vitiligo (n = 13, 8.5%) was prevalent in autoimmune/pigmentation disorders. Among all the patients with genetic mutations, one-quarter had a deleterious mutation in the LRBA gene, relating to the autoimmune and atopic skin lesions.

CONCLUSION: This rate of skin disorders in our cohort demonstrating these manifestations could be significant in CVID patients, and they are not rare. Low data of skin complications in CVID patients could be attributed to insufficient attention of physicians and also might alert dermatologists to perform immunological investigations in children with certain skin manifestations.

PMID:35084691 | DOI:10.1007/s10875-022-01211-x

Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:69-72. doi: 10.1111/pai.13634.

ABSTRACT

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110δ subunit and the ubiquitously expressed regulatory p85 α subunit of the phosphoinositide 3-kinase δ (PI3Kδ). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110δ inhibitors have been reported, certainly ameliorating these patients’ quality of life and prognosis.

PMID:35080319 | DOI:10.1111/pai.13634

Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:61-64. doi: 10.1111/pai.13632.

ABSTRACT

Inborn errors of immunity (IEI), also referred to as primary immunodeficiencies (PID), are disorders that, for the most part, result from mutations in genes involved in immune host defense and immune regulation. With the increased availability of high-throughput DNA sequencing and improved genomic data interpretation, the number of newly identified genes associated with IEI has exponentially increased over the last decade. Here, we focus on the newly described IEI associated with severe COVID-19 and SASH3 deficiency, the most recently reported IEI with impaired T-cell receptor (TCR) signaling.

PMID:35080321 | DOI:10.1111/pai.13632

Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:73-76. doi: 10.1111/pai.13635.

ABSTRACT

The complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management.

PMID:35080299 | DOI:10.1111/pai.13635

Pediatr Allergy Immunol. 2022 Jan;33 Suppl 27:65-68. doi: 10.1111/pai.13633.

ABSTRACT

Primary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.

PMID:35080318 | DOI:10.1111/pai.13633

NMC Case Rep J. 2021 Jun 12;8(1):253-259. doi: 10.2176/nmccrj.cr.2020-0234. eCollection 2021.

ABSTRACT

We report a rare case of primary central nervous system (CNS) lymphoma as methotrexate-associated lymphoproliferative disorders (MTX-LPD). A 75-year-old woman who had been treated for rheumatoid arthritis (RA) with MTX for 3 years was admitted to our hospital complaining of unsteady gait, nausea, and vomiting. T2-weighted image of magnetic resonance imaging (MRI) showed multiple high intensity mass-like lesions including right lateral, frontal and temporal lobes, and right cerebellar hemisphere. We performed surgical biopsy, and the pathological and immunohistochemical examinations identified T-cell lymphoma. The tumor regressed and the symptoms were resolved soon after MTX withdrawal. Primary CNS lymphoma due to MTX-LPD is a rare disease and only eight cases including ours are reported.

PMID:35079472 | PMC:PMC8769407 | DOI:10.2176/nmccrj.cr.2020-0234

J Clin Immunol. 2022 Jan 26. doi: 10.1007/s10875-021-01191-4. Online ahead of print.

ABSTRACT

PURPOSE: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency.

METHODS: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation.

RESULTS: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7 months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03).

CONCLUSION: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

PMID:35079916 | DOI:10.1007/s10875-021-01191-4