Manish Butte

Mult Scler. 2021 Jun 7:1352458520963896. doi: 10.1177/1352458520963896. Online ahead of print.

ABSTRACT

BACKGROUND: The cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway acts as a negative immune regulator of T-cell activation and promotes self-tolerance.

CASE: We report the first case of biopsy-proven central nervous system inflammatory demyelination in the context of primary immunodeficiency and a novel CTLA-4 variant.

CONCLUSION: This case has significant implications for the development of novel treatments for autoimmune conditions including multiple sclerosis and further emphasises the need for caution with clinical use of CTLA-4 immune checkpoint inhibitors in those with a history of inflammatory demyelination.

PMID:34097529 | DOI:10.1177/1352458520963896

Pharmacoepidemiol Drug Saf. 2021 Jun 7. doi: 10.1002/pds.5302. Online ahead of print.

ABSTRACT

PURPOSE: Most European influenza vaccine strategies target individuals at higher risk of complications, which include, among others, individuals aged ≥65 years and with chronic conditions. These individuals not only have a high-risk of post-infection complications but also could have lower capacity of acquiring adequate vaccine-induced protection. As such, chronic conditions and age could modify the effect of vaccines. This study aimed at assessing the potential effect modification of influenza vaccine effectiveness (IVE) by age and chronic conditions.

METHODS: We used eight-season data from the Portuguese vaccine effectiveness study. Every season, physicians at primary care units recruited patients with influenza-like illness. Clinical data and swabs were collected for Reverse Transverse Polymerase Chain Reaction (RT-PCR) detection of influenza. Trivalent inactivated IVE was estimated as 1 – odds ratio (OR) of being vaccinated in cases (RT-PCR positive for influenza) versus negative controls. ORs were obtained using a multivariable conditional logistic regression model, paired by week of onset within each season. Confounders were assessed by designing a specific causal diagram. Age (< 65 or ≥ 65 years) and chronic conditions (diabetes, cardiovascular disease, chronic renal disease, chronic hepatic disease, obesity, chronic respiratory disease, and congenital or acquired immunodeficiency) were studied as effect modifiers by including an interaction term in the regression models. Significance was established at 5%.

RESULTS: Point estimates indicate a higher IVE in the chronic condition strata compared to that in the no chronic condition strata. Regarding age, different results were obtained considering the virus type and (sub)type. When comparing the ≥65 years of age strata with the <65 years of age strata, we observed a higher IVE against A(H1N1)pdm09, an equal IVE against A(H3N2) and a lower IVE against B virus. However, all interaction terms were statistically insignificant, and this may be due to a small sample size.

CONCLUSION: The potential effect modification of age or chronic condition was not observed within our study. This article is protected by copyright. All rights reserved.

PMID:34096151 | DOI:10.1002/pds.5302

Front Immunol. 2021 May 21;12:665621. doi: 10.3389/fimmu.2021.665621. eCollection 2021.

ABSTRACT

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

PMID:34093558 | PMC:PMC8176954 | DOI:10.3389/fimmu.2021.665621

Pediatr Transplant. 2021 Jun 6:e14063. doi: 10.1111/petr.14063. Online ahead of print.

ABSTRACT

BACKGROUND: Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases.

METHODS: 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID.

RESULTS: Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12 months (range: 2.5-172 months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27 months (6 months-5 years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients.

CONCLUSIONS: We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.

PMID:34092004 | DOI:10.1111/petr.14063

Sci Immunol. 2021 Jun 4;6(60):eabd3774. doi: 10.1126/sciimmunol.abd3774.

ABSTRACT

Although CD8⁺ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)-derived antigen involves the generation and suppressive function of FoxP3⁺CD8⁺ T cells. FoxP3⁺CD8⁺ T_reg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGFβ, and retinoic acid contributed to the generation of gut-tropic CCR9⁺CD103⁺FoxP3⁺CD8⁺ T_regs Last, CD103-deficient CD8⁺ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3⁺CD8⁺ T_reg function. Our results describe a role for FoxP3⁺CD8⁺ T_regs in cross-tolerance in the intestine for which development requires intestinal cDC1.

PMID:34088744 | DOI:10.1126/sciimmunol.abd3774

J Allergy Clin Immunol. 2021 Jun 1:S0091-6749(21)00886-1. doi: 10.1016/j.jaci.2021.05.028. Online ahead of print.

ABSTRACT

BACKGROUND: Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited.

OBJECTIVE: To describe NRH prevalence, associated features and impact in patients with XLA.

METHODS: Medical records of all XLA patients referred to the NIH between 1994 and 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher’s exact test and Mann-Whitney test were used for statistical comparisons.

RESULTS: Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent at least one liver biopsy of whom 6 (29% of NIH XLA cohort) were NRH+. The median age at NRH diagnosis was 20y (17-31). Among patients who had liver biopsies, alkaline phosphatase (ALP) levels were only increased in NRH+ patients (p=0.04). Persistently low platelet count (<100k/μL for more than 6 months), mildly to highly elevated hepatic venous pressure gradient (HVPG) and either hepatomegaly and/or splenomegaly were present in all NRH+ patients. In opposition, persistently low platelet counts were not seen in NRH- patients, and hepatosplenomegaly only observed in one NRH- patient. HVPG was normal in the only NRH- patient tested. All-cause mortality was higher among NRH+ patients (5/6, 83%) than in the rest of the cohort (1/15, 7% among NRH- and Unknown patients, p=0.002).

CONCLUSION: NRH is an underreported, frequent and severe complication in XLA, which is associated with increased morbidity and mortality.

PMID:34087243 | DOI:10.1016/j.jaci.2021.05.028

Front Immunol. 2021 May 14;12:667727. doi: 10.3389/fimmu.2021.667727. eCollection 2021.

NO ABSTRACT

PMID:34084169 | PMC:PMC8168433 | DOI:10.3389/fimmu.2021.667727

Eur J Hum Genet. 2021 Jun 1. doi: 10.1038/s41431-021-00851-8. Online ahead of print.

ABSTRACT

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism.

PMID:34075209 | DOI:10.1038/s41431-021-00851-8

Cancers (Basel). 2021 May 27;13(11):2630. doi: 10.3390/cancers13112630.

ABSTRACT

(1) Background: Blockade of the PD-1/PD-L1 pathway has revolutionized the oncology field in the last decade. However, the proportion of patients experiencing a durable response is still limited. In the current study, we performed an extensive immune monitoring in patients with stage III/IV melanoma and stage IV UC who received anti-PD-1 immunotherapy with SBRT. (2) Methods: In total 145 blood samples from 38 patients, collected at fixed time points before and during treatment, were phenotyped via high-parameter flow cytometry, luminex assay and UPLC-MS/MS. (3) Results: Baseline systemic immunity in melanoma and UC patients was different with a more prominent myeloid compartment and a higher neutrophil to lymphocyte ratio in UC. Proliferation (Ki67⁺) of CD8⁺ T-cells and of the PD-1⁺/PD-L1⁺ CD8⁺ subset at baseline correlated with progression free survival in melanoma. In contrast a higher frequency of PD-1/PD-L1 expressing non-proliferating (Ki67^–) CD8⁺ and CD4⁺ T-cells before treatment was associated with worse outcome in melanoma. In UC, the expansion of Ki67⁺ CD8⁺ T-cells and of the PD-L1⁺ subset relative to tumor burden correlated with clinical outcome. (4) Conclusion: This study reveals a clearly different immune landscape in melanoma and UC at baseline, which may impact immunotherapy response. Signatures of proliferation in the CD8⁺ T-cell compartment prior to and early after anti-PD-1 initiation were positively correlated with clinical outcome in both cohorts. PD-1/PD-L1 expression on circulating immune cell subsets seems of clinical relevance in the melanoma cohort.

PMID:34071888 | DOI:10.3390/cancers13112630

Viruses. 2021 May 9;13(5):867. doi: 10.3390/v13050867.

ABSTRACT

BACKGROUND: The impact of respiratory virus infection in patients diagnosed with ataxia-telangiectasia (A-T) has not been well studied.

METHODS: A prospective case control study was performed at a National Reference Unit for Primary Immunodeficiency in Spain (from November 2018 to July 2019), including patients younger than 20 years. Symptom questionnaires and nasopharyngeal swabs from multiple respiratory viruses’ polymerase chain reaction were collected monthly, and between visits in case of symptoms.

RESULTS: Twenty-two individuals were included (11 patients; 11 controls); 164 samples were obtained (81 patients; 84 controls). Patients presented respiratory symptoms more frequently compared with controls (26.5% vs. 3.5%; p < 0.01). Viral detection was observed in 23 (27.3%) episodes in patients and in 15 (17.8%) episodes in controls (p = 0.1). Rhinovirus was the most frequent virus in patients and controls (60% and 53.3%, respectively). Episodes with positive viral detection had associated symptoms in 54% of patients and 18% of controls (p = 0.07). However, patients with A-T presented a similar rate of symptoms during episodes with positive and negative viral detection (26% vs. 27%). The median points given for each questionnaire during symptomatic episodes with negative viral detection were 13/23 points, and during symptomatic positive detection, 7.5/23 points (p = 0.1). In the control group, all but two were asymptomatic during positive viral episodes (score: 2/23 and 3/23 points). Symptomatic episodes, with either positive or negative viral detection, were associated with lower IgA and higher IgM titers and higher CD8+ counts (p < 0.05), particularly when these episodes were moderate/severe.

CONCLUSIONS: Patients with A-T more frequently present symptomatic viral infections than controls, especially those with lower IgA and higher IgM titers and higher CD8+ counts.

PMID:34065066 | DOI:10.3390/v13050867