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Genes (Basel). 2023 Dec 2;14(12):2172. doi: 10.3390/genes14122172.

ABSTRACT

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although immunotherapy is effective for some patients, most find it difficult to benefit from it. This study aims to explore the impact of specific immune pathways and their regulated molecular mechanisms in TNBC. The gene expression data of breast cancer patients were obtained from the TCGA and METABRIC databases. Gene set variation analysis (GSVA) revealed specific upregulation or abnormal expression of immunodeficiency pathways in TNBC patients. Multi-omics data showed significant differential expression of Primary Immunodeficiency Genes (PIDGs) in TNBC patients, who are prone to genomic-level variations. Consensus clustering was used in two datasets to classify patients into two distinct molecular subtypes based on PIDGs expression patterns, with each displaying different biological features and immune landscapes. To further explore the prognostic characteristics of PIDGs-regulated molecules, we constructed a four-gene prognostic PIDG score model and a nomogram using least absolute shrinkage and selection operator (LASSO) regression analysis in combination with clinicopathological parameters. The PIDG score was closely associated with the immune therapy and drug sensitivity of TNBC patients, providing potential guidance for clinical treatment. Particularly noteworthy is the close association of this scoring with RNA modifications; patients with different scores also exhibited different mutation landscapes. This study offers new insights for the clinical treatment of TNBC and for identifying novel prognostic markers and therapeutic targets in TNBC.

PMID:38136994 | DOI:10.3390/genes14122172

Stem Cell Res. 2023 Dec 7;74:103269. doi: 10.1016/j.scr.2023.103269. Online ahead of print.

ABSTRACT

Chronic granulomatous disease (CGD) is a rare X-linked recessive primary immunodeficiency disease (PID). Herein, a human induced pluripotent stem cell (iPSC) line was generated from the peripheral blood mononuclear cells (PBMCs) of a CGD patient with a mutation (c.785_786delTT) in the CYBB gene. These iPSCs showed the expression of pluripotency markers, the ability to differentiate into three germ layers. They offer a promising technique for studying the pathogenesis and conducting drug screening for CGD patients.

PMID:38134578 | DOI:10.1016/j.scr.2023.103269

Neurol Neuroimmunol Neuroinflamm. 2024 Mar;11(2):e200191. doi: 10.1212/NXI.0000000000200191. Epub 2023 Dec 22.

ABSTRACT

OBJECTIVES: Complement factor I (CFI) deficiency is a rare autosomal recessive inborn error of immunity. In this report, we highlight that complete CFI deficiency may present with isolated and severe CNS inflammation without associated systemic features nor prior non-CNS episodes. This inflammation may respond to complement blockade therapy.

METHODS: This is a case description of a young girl with severe longitudinal transverse myelitis treated with aggressive immunotherapy that included eculizumab. Published cases of CFI-associated CNS inflammation were reviewed and discussed.

RESULTS: A primary immunodeficiency panel revealed 2 germline pathogenic variants in the CFI gene. Further complement testing of the index case and her family confirmed complete CFI deficiency.

DISCUSSION: We describe a unique case of severe spinal inflammation secondary to complete CFI deficiency. Although rare, isolated CNS inflammation may be the primary manifestation of complete CFI deficiency. To halt the uncontrolled complement-mediated inflammation associated with CFI deficiency, prompt targeted blockade of the complement pathway using eculizumab may be life changing in the acute phase. Long-lasting blockade of the complement pathway is also essential to prevent relapse in this subgroup of patients.

PMID:38134378 | DOI:10.1212/NXI.0000000000200191

Cureus. 2023 Nov 21;15(11):e49168. doi: 10.7759/cureus.49168. eCollection 2023 Nov.

ABSTRACT

Immune thrombocytopenic purpura is one of the most common causes of low platelet count in the pediatric population. Secondary thrombocytopenia has a wide differential diagnosis in children, including rheumatological, hematological, and immunological etiologies. Underlying etiologies must be excluded if suspected before labeling the patient as primary thrombocytopenia. Here, we report two siblings with persistent and profound thrombocytopenia. A 10-year-old girl presented with profound and treatment-refractory thrombocytopenia. Given the patient’s family history of thrombocytopenia of unknown pathology in her older brother, immune dysregulation-related thrombocytopenia was suspected. Whole exome sequencing confirmed a previously reported pathogenic variant in the NFKB1 gene linked to common variable immunodeficiency 12 (CVID-12) diagnosis for both patients.

PMID:38130541 | PMC:PMC10733976 | DOI:10.7759/cureus.49168

J Clin Immunol. 2023 Dec 22;44(1):28. doi: 10.1007/s10875-023-01632-2.

ABSTRACT

PURPOSE: Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%.

METHODS: This phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19-50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability (“tolerable” infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs.

RESULTS: Overall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs.

CONCLUSION: fSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases. Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

PMID:38129731 | DOI:10.1007/s10875-023-01632-2

J Clin Immunol. 2023 Dec 22;44(1):26. doi: 10.1007/s10875-023-01620-6.

ABSTRACT

PURPOSE: Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive combined immunodeficiency. The detailed immune responses are not explored widely. We investigated known and novel immune alterations in lymphocyte subpopulations and their association with clinical symptoms in a well-defined ICF cohort.

METHODS: We recruited the clinical findings from twelve ICF1 and ICF2 patients. We performed detailed immunological evaluation, including lymphocyte subset analyses, upregulation, and proliferation of T cells. We also determined the frequency of circulating T follicular helper (cT_FH) and regulatory T (Treg) cells and their subtypes by flow cytometry.

RESULTS: There were ten ICF1 and two ICF2 patients. We identified two novel homozygous missense mutations in the ZBTB24 gene. Respiratory tract infections were the most common recurrent infections among the patients. Gastrointestinal system (GIS) involvements were observed in seven patients. All patients received intravenous immunoglobulin replacement therapy and antibacterial prophylaxis; two died during the follow-up period. Immunologically, CD4⁺ T-cell counts, percentages of recent thymic emigrant T cells, and naive CD4⁺ T decreased in two, five, and four patients, respectively. Impaired T-cell proliferation and reduced CD25 upregulation were detected in all patients. These changes were more prominent in CD8⁺ T cells. GIS involvements negatively correlated with CD3⁺ T-, CD3⁺CD4⁺ T-, CD16⁺CD56⁺ NK-cell counts, and CD4⁺/CD8⁺ T-cell ratios. Further, we observed expanded cT_FH cells and reduced Treg and follicular regulatory T cells with a skewing to a T_H2-like phenotype in all tested subpopulations.

CONCLUSION: The ICF syndrome encompasses various manifestations affecting multiple end organs. Perturbed T-cell responses with increased cT_FH and decreased Treg cells may provide further insight into the immune aberrations observed in ICF syndrome.

PMID:38129713 | DOI:10.1007/s10875-023-01620-6

J Clin Immunol. 2023 Dec 22;44(1):23. doi: 10.1007/s10875-023-01615-3.

ABSTRACT

PURPOSE: Non-tuberculous mycobacteria (NTM) infections in hematopoietic stem cell transplantation (HSCT) recipients represent a diagnostic and therapeutic challenge. Here, we aimed to review and analyze current literature on incidence, clinical presentation, and outcome of NTM infection after allogeneic HSCT.

METHODS: We performed a systematic review and meta-analysis of available literature regarding NTM infection in children and adults receiving allogeneic HSCT.

RESULTS: We identified 56 articles eligible for the analysis. Among 15 studies, describing 15,798 allogeneic HSCT, we estimated a prevalence of 1.26% (95% CI 0.72, 1.93) of NTM after transplant. Analysis of 175 patients with NTM infection showed a median time of diagnosis of 318 days after HSCT, an increased prevalence in adults (82.9%), and a most frequent pulmonary involvement (44%). Comparison between children and adults revealed an earlier post-transplant disease onset (median 130 days vs 287 days) and most frequent non-pulmonary presentation in children. A vast heterogeneity of therapeutic approach reflected the lack of universal recommendations regarding drug combination and duration of therapy. Overall, NTM-related mortality accounted for 33% in this systematic review.

CONCLUSION: Although rare, NTM infections can complicate post-transplant course with a high mortality rate in children and adults. The lack of prospective studies and guidelines prevents identification of risk factors and therapeutic recommendations.

PMID:38129624 | DOI:10.1007/s10875-023-01615-3

J Clin Immunol. 2023 Dec 22;44(1):13. doi: 10.1007/s10875-023-01619-z.

ABSTRACT

Human BCL10 deficiency causes combined immunodeficiency with bone marrow transplantation as its only curative option. To date, there are four homozygous mutations described in the literature that were identified in four unrelated patients. Here, we describe a fifth patient with a novel mutation and summarize what we have learned about BCL10 deficiency. Due to the severity of the disease, accurate knowledge of its clinical and immunological characteristics is instrumental for early diagnosis and adequate clinical management of the patients.

PMID:38129623 | DOI:10.1007/s10875-023-01619-z

J Clin Immunol. 2023 Dec 22;44(1):21. doi: 10.1007/s10875-023-01618-0.

ABSTRACT

PURPOSE: Common variable immunodeficiency (CVID) is a primary antibody deficiency that commonly manifests as recurrent infections. Many CVID patients also suffer from immune dysregulation, an inflammatory condition characterized by polyclonal lymphocytic tissue infiltration and associated with increased morbidity and mortality. The genetic cause is unknown in most CVID patients and epigenetic alterations may contribute to the broad range of clinical manifestations. MicroRNAs are small non-coding RNAs that are involved in epigenetic modulation and may contribute to the clinical phenotype in CVID.

METHODS: Here, we determined the circulating microRNAome and plasma inflammatory proteins of a cohort of CVID patients with various levels of immune dysregulation and compared them to healthy controls. A set of deregulated microRNAs was validated by qPCR and correlated to inflammatory proteins and clinical findings.

RESULTS: Levels of microRNA-34a correlated with 11 proteins such as CXCL9, TNF, and IL10, which were predicted to be biologically connected. Moreover, there was a negative correlation between mir-34 levels and the number of naïve CD4 T cells in CVID.

CONCLUSION: Collectively, our data show that microRNAs correlate with the inflammatory response in CVID. Further investigations are needed to elucidate the role of miRNAs in the development of CVID-related immune dysregulation.

PMID:38129593 | DOI:10.1007/s10875-023-01618-0

J Clin Immunol. 2023 Dec 22;44(1):27. doi: 10.1007/s10875-023-01608-2.

ABSTRACT

Zeta-chain associated protein kinase 70 kDa (ZAP70) combined immunodeficiency (CID) is an autosomal recessive severe immunodeficiency that is characterized by abnormal T-cell receptor signaling. Children with the disorder typically present during the first year of life with diarrhea, failure to thrive, and recurrent bacterial, viral, or opportunistic infections. To date, the only potential cure is hematopoietic stem cell transplant (HSCT). The majority of described mutations causing disease occur in the homozygous state, though heterozygotes are reported without a clear understanding as to how the individual mutations interact to cause disease. This case describes an infant with novel ZAP-70 deficiency mutations involving the SH2 and kinase domains cured with allogeneic HSCT utilizing a reduced-intensity conditioning regimen and graft manipulation. We then were able to further elucidate the molecular signaling alterations imparted by these mutations that lead to altered immune function. In order to examine the effect of these novel compound ZAP70 heterozygous mutations on T cells, Jurkat CD4⁺ T cells were transfected with either wild type, or with individual ZAP70 R37G and A507T mutant constructs. Downstream TCR signaling events and protein localization results link these novel mutations to the expected immunological outcome as seen in the patient’s primary cells. This study further characterizes mutations in the ZAP70 gene as combined immunodeficiency and the clinical phenotype.

PMID:38129328 | DOI:10.1007/s10875-023-01608-2