Manish Butte

Clin Immunol. 2023 Aug 29:109748. doi: 10.1016/j.clim.2023.109748. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency (CVID) has been recognised as the most common primary immunodeficiency in adulthood, and is characterised by increased susceptibility to infection, autoimmunity and increased risk of malignancies. Although ocular manifestations are not common in CVID, rare associated inflammatory eye conditions have been reported including submacular choroiditis.

OBJECTIVE: To report a case of punctate inner choroidopathy in a patient with common variable immunodeficiency.

CASE PRESENTATION: A 40-year-old lady with CVID and associated autoimmune thrombocytopenia, who was treated with immunoglobulin replacement and Eltrombopag, experienced gradually deteriorating right eye vision. Fundal examination and optical coherence tomography (OCT) revealed right multifocal retinal choroidal lesions consistent with a diagnosis of unilateral punctate inner choroidopathy with secondary choroidal neovascularisation (CNV).. Anti-VEGF injections led to stabilised fundal appearances. Genetic testing revealed a heterozygous sequence change c.260 T > Ap.(IIe87Asn), pathogenic variant in the Tumour Necrosis Factor Superfamily 13B (TNFRSF13B) gene, which is reported as being associated with ~10% of CVID cases.

CONCLUSION: Autoimmunity may be the dominant clinical presenting feature of CVID. Punctuate inner choroidopathy is an idiopathic inflammatory chorioretinopathy, and to the best of our knowledge, has not been previously reported in CVID. A better understanding of the molecular bases of autoimmune diseases in CVID may provide novel therapeutic targets for autoimmune diseases in this patient population.

PMID:37652172 | DOI:10.1016/j.clim.2023.109748

Front Immunol. 2023 Aug 14;14:1225610. doi: 10.3389/fimmu.2023.1225610. eCollection 2023.

ABSTRACT

CD30 is expressed on Hodgkin lymphomas (HL), many non-Hodgkin lymphomas (NHLs), and non-lymphoid malignancies in children and adults. Tumor expression, combined with restricted expression in healthy tissues, identifies CD30 as a promising immunotherapy target. An anti-CD30 antibody-drug conjugate (ADC) has been approved by the FDA for HL. While anti-CD30 ADCs and chimeric antigen receptors (CARs) have shown promise, their shortcomings and toxicities suggest that alternative treatments are needed. We developed novel anti-CD30 x anti-CD3 bispecific antibodies (biAbs) to coat activated patient T cells (ATCs) ex vivo prior to autologous re-infusions. Our goal is to harness the dual specificity of the biAb, the power of cellular therapy, and the safety of non-genetically modified autologous T cell infusions. We present a comprehensive characterization of the CD30 binding and tumor cell killing properties of these biAbs. Five unique murine monoclonal antibodies (mAbs) were generated against the extracellular domain of human CD30. Resultant anti-CD30 mAbs were purified and screened for binding specificity, affinity, and epitope recognition. Two lead mAb candidates with unique sequences and CD30 binding clusters that differ from the ADC in clinical use were identified. These mAbs were chemically conjugated with OKT3 (an anti-CD3 mAb). ATCs were armed and evaluated in vitro for binding, cytokine production, and cytotoxicity against tumor lines and then in vivo for tumor cell killing. Our lead mAb was subcloned to make a Master Cell Bank (MCB) and screened for binding against a library of human cell surface proteins. Only huCD30 was bound. These studies support a clinical trial in development employing ex vivo-loading of autologous T cells with this novel biAb.

PMID:37646042 | PMC:PMC10461807 | DOI:10.3389/fimmu.2023.1225610

Cancer Res Commun. 2023 Aug 25;3(8):1648-1661. doi: 10.1158/2767-9764.CRC-23-0193. eCollection 2023 Aug.

ABSTRACT

Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical C_max, if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation.

SIGNIFICANCE: Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

PMID:37637936 | PMC:PMC10452929 | DOI:10.1158/2767-9764.CRC-23-0193

Front Endocrinol (Lausanne). 2023 Aug 10;14:1209577. doi: 10.3389/fendo.2023.1209577. eCollection 2023.

ABSTRACT

INTRODUCTION: The chromosome 22q11.2 deletion syndrome comprises phenotypically similar diseases characterized by abnormal development of the third and fourth branchial arches, resulting in variable combinations of congenital heart defects, dysmorphisms, hypocalcemia, palatal dysfunction, developmental or neuropsychiatric disorders, and impairment of the immune system due to thymic dysfunction. Other genetic syndromes, often called DiGeorge-like, share clinical and immunological features with 22q11.2 deletion syndrome. This syndrome has been rarely associated with malignancies, mainly hematological but also hepatic, renal, and cerebral. Rarely, malignancies in the head and neck region have been described, although no aggregate of data on the development of thyroid neoplasms in patients with this clinical phenotype has been conducted so far.

MATERIALS AND METHODS: To characterize this possible association, a multicenter survey was made. Thus, we present a case series of five pediatric patients with 22q11.2 deletion syndrome or DiGeorge-like syndrome who were occasionally found with confirmed or highly suspected neoplasms of the thyroid gland during their follow-up. In three cases, malignancies were histologically confirmed, but their outcome was good due to an early recognition of suspicious nodules and precocious surgery.

CONCLUSIONS: This study underlines for clinicians the higher risk of neoplasms in the head and neck district for patients affected by these syndromes. It also emphasizes the importance of a prolonged clinical and ultrasound follow-up for patients with this clinical and immunological phenotype.

PMID:37635986 | PMC:PMC10450035 | DOI:10.3389/fendo.2023.1209577

J Affect Disord. 2023 Aug 24:S0165-0327(23)01093-5. doi: 10.1016/j.jad.2023.08.113. Online ahead of print.

ABSTRACT

OBJECTIVE: To study the relationship between clock genes and Major Depressive Disorder (MDD).

METHODS: GEO database was used to obtain the chip data and clinical information of datasets GSE98793, GSE39653 and GSE52790. The differentially expressed clock genes were found through the analysis of the differentially expressed genes between MDD and healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG) enrichment analysis were performed on the differential expressed clock genes. Lasso Regression and Support Vector Machine (SVM) method were used for screening the differential expressed clock genes. Logistic regression was used to establish a diagnostic model for depression with the screened genes. Receiver Operating Characteristic (ROC) Curve was used to verify the model. Gene differential expression analysis was performed for MDD with high scores and MDD with low scores in the diagnostic model. Gene Set Enrichment Analysis (GSEA) enrichment analysis was performed for differentially expressed genes. Single-gene GSEA was used to analyze each gene in the model separately. Cibersort method was used to analyze the immune infiltration of MDD and healthy controls, and the correlation between immune cells and clock genes was analyzed. Cytoscape was used to analyze the clock gene interaction network. The DGIdb website was used to predict potentially effective therapeutic drugs for clock genes closely related to MDD.

RESULTS: Six genes were identified by differential expression analysis of clock genes between MDD and healthy controls. GO and KEGG enrichment analysis of 6 genes showed that their pathways were concentrated such as circadian rhythm, rhythmic process, TGF – beta signaling pathway, longevity regulating pathway-multiple species, adipocytokine signaling pathway and so on. Lasso regression and SVM were used to screen out 5 clock genes (HDAC1, ID3, NFIL3, PRKAA1, TNF) for MDD. The diagnostic model of depression was established according to the 5 clock genes. The area under the curve (AUC) of the established depression diagnostic model was 0.686. Gene difference analysis was performed between MDD patients with high score of clock gene diagnostic model and MDD patients with low score. GSEA was performed for the differential genes showed that the most enriched pathways were:adipocytokine signaling pathway, TGF beta signaling pathway, oxidative phosphorylation, primary immunodeficiency, and so on. The single gene GSEA showed that the most enriched pathways were Toll like receptor signaling pathway, glucolipid metabolism, amino acid metabolism, neuroactive ligand receptor interaction, and so on. The results of immune infiltration analysis showed that NK cells resting and Macrophages M2 were different between MDD and control groups. In MDD, the gene closely related to NK cells resting was HDAC1, and the genes closely related to Macrophages M2 were HDAC1 and NFIL3. The RNA interactions network of clock genes shows that the regulation process is complex, which can provide a reference for subsequent related research. Potential therapeutic drugs predict display, among the 5 clock genes, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.

CONCLUSION: Among all CLOCK genes, HDAC1, ID3, NFIL3, PRKAA1, TNF are closely related to MDD. Among them, TNF, HDAC1, and PRKAA1 may have potential effective therapeutic drugs.

PMID:37633529 | DOI:10.1016/j.jad.2023.08.113

J Clin Med. 2023 Aug 21;12(16):5427. doi: 10.3390/jcm12165427.

ABSTRACT

BACKGROUND: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is known as a prolonged immunodeficiency that occurs after severe infection. Few studies have demonstrated a direct relationship between PIICS and physical dysfunction in post-intensive care syndrome (PICS). We herein investigated how each component of PICS was affected by the diagnosis of PIICS during hospitalization and examined the relationship between PIICS and PICS using PICS assessments performed at the Hitachi General Hospital PICS Clinic.

METHODS: The 273 patients who visited the PICS clinic at one month after discharge from the ICU at Hitachi General Hospital were included in the study. We used the diagnostic criteria for PIICS described in previous studies. At least two of the following blood test values on day 14 of hospitalization had to be met for a diagnosis of PIICS: C-reactive protein (CRP) > 2.0 mg/dL, albumin (Alb) < 3.0 g/dL, and lymphocytes (Lym) < 800/μL. Blood test values closest to day 14 out of 11-17 days of hospitalization were used. The primary outcome was a Barthel Index (BI) < 90, while secondary outcomes were the results of various PICS assessments, including mental and cognitive impairments, performed at the PICS clinic. We supplemented missing data with multiple imputations by chained equations. We performed a nominal logistic regression analysis with age, sex, BMI, SOFA, and the presence of PIICS as variables for BI < 90.

RESULTS: Forty-three out of two hundred seventy-three PICS outpatients met the diagnostic criteria for PIICS during hospitalization. In comparisons with non-PIICS patients, significantly higher severity scores for APACHE II and SOFA and a longer hospital stay were observed in PIICS patients, suggesting a higher clinical severity. The primary outcome, BI, was lower in the PIICS group (97.5 (58.5, 100) vs. 100 (95, 100), p = 0.008), as were the secondary outcomes (FSS-ICU: 35 (31, 35) vs. 35 (35, 35), MRC score: 55 (50.25, 58) vs. 58 (53, 60), grip strength: 16.45 (9.2, 25.47) vs. 20.4 (15.3, 27.7)). No significant differences were noted in mental or cognitive function assessments, such as HADS, IES-R, and SMQ. A multivariable analysis supplemented with missing data revealed that PIICS (odds ratio: 1.23 (1.08-1.40 p = 0.001) and age (odds ratio: 1.007 (1.004-1.01), p < 0.001) correlated with BI < 90, independent of clinical severity such as sequential organ failure assessment (SOFA). Similar results were obtained in the sensitivity analysis excluding missing data.

CONCLUSIONS: The present study revealed a strong relationship between PIICS and post-discharge PICS physical dysfunction in patients requiring intensive care.

PMID:37629468 | DOI:10.3390/jcm12165427

Children (Basel). 2023 Aug 8;10(8):1358. doi: 10.3390/children10081358.

ABSTRACT

Transient hypogammaglobulinemia of infancy (THI) is a primary immunodeficiency caused by a temporary decline in serum immunoglobulin G (IgG) levels greater than two standard deviations below the mean age-specific reference values in infants between 5 and 24 months of age. Preterm infants are particularly susceptible to THI, as IgG is only transferred across the placenta from mother to infant during the third trimester of pregnancy. This study aimed to conduct a systematic review of the diagnostic criteria for transient hypogammaglobulinemia of infancy. Systematic review: Three electronic databases (PubMed, MEDLINE, and Google Scholar) were manually searched from September 2021 to April 2022. Abstracts were screened to assess their fit to the inclusion criteria. Data were extracted from the selected studies using an adapted extraction tool (Cochrane). The studies were then assessed for bias using an assessment tool adapted from Cochrane. Of the 215 identified articles, 16 were eligible for examining the diagnostic criteria of THI. These studies were also assessed for bias in the six domains. A total of five studies (31%) had a low risk of bias, while four studies (25%) had a high risk of bias, and bias in the case of seven studies (44%) was unclear. We conclude that THI is only definitively diagnosed after abnormal IgG levels normalise. Hence, THI is not a benign condition, and monitoring for subsequent recurrent infections must be conducted. The diagnostic criteria should also include vaccine and isohaemagglutinin responses to differentiate THI from other immunological disorders in infants.

PMID:37628357 | DOI:10.3390/children10081358

Cells. 2023 Aug 12;12(16):2055. doi: 10.3390/cells12162055.

ABSTRACT

The human immune system is a complex network of cells, tissues, and molecules that work together to defend the body against pathogens and maintain overall health. However, in some individuals, the immune system fails to function correctly, leading to immunodeficiencies. Immunodeficiencies can be classified into primary (PID) and secondary (SID) types, each with distinct underlying causes and manifestations. Toll-like receptors (TLRs), as key components of the immune system, have been implicated in the pathogenesis of both PID and SID. In this study, we aim to unravel the intricate involvement of TLR2, TLR4, TLR3, TLR7, TLR8, and TLR9 in the immunopathogenesis of common variable immunodeficiency-CVID (as PID)-and chronic lymphocytic leukemia-CLL (as SID). The obtained results indicate a significant increase in the percentage of all tested subpopulations of T lymphocytes and B lymphocytes showing positive expression of all analyzed TLRs in patients with CVID and CLL compared to healthy volunteers, constituting the control group, which is also confirmed by analysis of the concentration of soluble forms of these receptors in the plasma of patients. Furthermore, patients diagnosed with CVID are characterized by the percentage of all lymphocytes showing positive expression of the tested TLR2, TLR4, TLR3, and TLR9 and their plasma concentrations in relation to patients with CLL. By investigating the functions and interactions of TLRs within the immune system, we seek to shed light on their critical role in the development and progression of these immunodeficiencies. Through a comprehensive analysis of the literature and presented experimental data, we hope to deepen our understanding of the complex mechanisms by which TLRs contribute to the pathogenesis of PID and SID. Ultimately, our findings may provide valuable insights into developing targeted therapeutic strategies to mitigate the impact of these disorders on those affected by immunodeficiency.

PMID:37626865 | DOI:10.3390/cells12162055

J Mol Med (Berl). 2023 Aug 25. doi: 10.1007/s00109-023-02359-8. Online ahead of print.

ABSTRACT

The transcription factor GATA2 is involved in human diseases ranging from hematopoietic disorders, to cancer, to infectious diseases. GATA2 is one of six GATA-family transcription factors that act as pioneering transcription factors which facilitate the opening of heterochromatin and the subsequent binding of other transcription factors to induce gene expression from previously inaccessible regions of the genome. Although GATA2 is essential for hematopoiesis and lymphangiogenesis, it is also expressed in other tissues such as the lung, prostate gland, gastrointestinal tract, central nervous system, placenta, fetal liver, and fetal heart. Gene or transcriptional abnormalities of GATA2 causes or predisposes patients to several diseases including the hematological cancers acute myeloid leukemia and acute lymphoblastic leukemia, the primary immunodeficiency MonoMAC syndrome, and to cancers of the lung, prostate, uterus, kidney, breast, gastric tract, and ovaries. Recent data has also linked GATA2 expression and mutations to responses to infectious diseases including SARS-CoV-2 and Pneumocystis carinii pneumonia, and to inflammatory disorders such as atherosclerosis. In this article we review the role of GATA2 in the etiology and progression of these various diseases.

PMID:37624387 | DOI:10.1007/s00109-023-02359-8

N Engl J Med. 2023 Aug 24;389(8):733-748. doi: 10.1056/NEJMra2301594.

NO ABSTRACT

PMID:37611123 | DOI:10.1056/NEJMra2301594