Manish Butte

Scand J Gastroenterol. 2024 Jul 15:1-7. doi: 10.1080/00365521.2024.2374395. Online ahead of print.

ABSTRACT

AIM: Primary immunodeficiencies (PIDs) are a heterogeneous disorder group characterized by an impaired immune system, leading to an increased susceptibility to infections and a wide range of clinical manifestations, including gastrointestinal (GI) complications. This study aimed to assess the GI manifestations of PID patients and highlight the significance of atypical gastrointestinal symptoms in the early diagnosis of these patients.

METHODS: A retrospective analysis was conducted on pediatric patients diagnosed with PIDs at Selcuk University Medical Faculty from 2011 to 2021. The study focused on demographic data, clinical presentation, genetic mutations, and GI manifestations, including endoscopic evaluation. Patients were categorized according to the International Union of Immunological Societies (IUIS) PID classifications. Statistical analyses were performed to identify significant associations between PID types and GI manifestations.

RESULTS: The cohort comprised 101 patients, with 46% presenting with GI symptoms, including malnutrition and chronic diarrhea, as the most common findings. Primary antibody deficiency (PAD) emerged as the most prevalent PID with GI involvement, followed by combined immunodeficiencies (CID) with associated or syndromic features. Endoscopic evaluations revealed inflammatory bowel disease (IBD)-like colitis in a significant subgroup of patients. The analysis showed that some GI symptoms were more common in specific PID categories, highlighting the importance of early gastroenterological assessment in PID patients.

CONCLUSION: Recognition of common GI symptoms in pediatric patients with PIDs may facilitate early diagnosis and prompt multidisciplinary management, potentially improving patient outcomes. The study highlights the necessity of considering PIDs in diagnosing persistent or severe GI symptoms in children.

PMID:39007903 | DOI:10.1080/00365521.2024.2374395

Biol Aujourdhui. 2024;218(1-2):9-18. doi: 10.1051/jbio/2024005. Epub 2024 Jul 15.

ABSTRACT

Systemic lupus erythematosus (SLE) presents a complex clinical landscape with diverse manifestations, suggesting a multifactorial etiology. However, the identification of rare monogenic forms of the disease has shed light on specific genetic defects underlying SLE pathogenesis, offering valuable insights into its underlying mechanisms and clinical heterogeneity. By categorizing these monogenic forms based on the implicated signaling pathways, such as apoptotic body clearance, type I interferon signaling, JAK-STAT pathway dysregulation, innate immune receptor dysfunction and lymphocytic abnormalities, a more nuanced understanding of SLE’s molecular basis emerges. Particularly in pediatric populations, where monogenic forms are more prevalent, routine genetic testing becomes increasingly important, with a diagnostic yield of approximately 10% depending on the demographic and methodological factors involved. This approach not only enhances diagnostic accuracy but also informs personalized treatment strategies tailored to the specific molecular defects driving the disease phenotype.

PMID:39007772 | DOI:10.1051/jbio/2024005

Front Cell Infect Microbiol. 2024 Jun 28;14:1408245. doi: 10.3389/fcimb.2024.1408245. eCollection 2024.

ABSTRACT

While simian immunodeficiency virus (SIV) infection is non-pathogenic in naturally infected African nonhuman primate hosts, experimental or accidental infection in rhesus macaques often leads to AIDS. Baboons, widely distributed throughout Africa, do not naturally harbor SIV, and experimental infection of baboons with SIVmac results in transient low-level viral replication. Elucidation of mechanisms of natural immunity in baboons could uncover new targets of antiviral intervention. We tested the hypothesis that an SIVmac adapted to replicate in baboon primary cells will gain the capacity to establish chronic infections in vivo. Here, we generated SIVmac variants in baboon cells through serial passage in PBMC from different donors (SIVbn-PBMC s1), in PBMC from the same donors (SIVbn-PBMC s2), or in isolated CD4 cells from the same donors used for series 2 (SIVbn-CD4). While SIVbn-PBMC s1 and SIVbn-CD4 demonstrated increased replication capacity, SIVbn-PBMC s2 did not. Pharmacological blockade of CCR5 revealed SIVbn-PBMC s1 could more efficiently use available CCR5 than SIVmac, a trait we hypothesize arose to circumvent receptor occupation by chemokines. Sequencing analysis showed that all three viruses accumulated different types of mutations, and that more non-synonymous mutations became fixed in SIVbn-PBMC s1 than SIVbn-PBMC s2 and SIVbn-CD4, supporting the notion of stronger fitness pressure in PBMC from different genetic backgrounds. Testing the individual contribution of several newly fixed SIV mutations suggested that is the additive effect of these mutations in SIVbn-PBMC s1 that contributed to its enhanced fitness, as recombinant single mutant viruses showed no difference in replication capacity over the parental SIVmac239 strain. The replicative capacity of SIVbn-PBMC passage 4 (P4) s1 was tested in vivo by infecting baboons intravenously with SIVbn-PBMC P4 s1 or SIVmac251. While animals infected with SIVmac251 showed the known pattern of transient low-level viremia, animals infected with SIVbn-PBMC P4 s1 had undetectable viremia or viral DNA in lymphoid tissue. These studies suggest that adaptation of SIV to grow in baboon primary cells results in mutations that confer increased replicative capacity in the artificial environment of cell culture but make the virus unable to avoid the restrictive factors generated by a complex multicellular organism.

PMID:39006742 | PMC:PMC11239360 | DOI:10.3389/fcimb.2024.1408245

J Pharm Sci. 2024 Jul 11:S0022-3549(24)00233-8. doi: 10.1016/j.xphs.2024.06.016. Online ahead of print.

ABSTRACT

Organoids are small, self-organizing three-dimensional cell cultures that are derived from stem cells or primary organs. These cultures replicate the complexity of an organ, which cannot be achieved by single-cell culture systems. Organoids can be used in testing of new drugs instead of animals. Development and validation of organoids is thus important to reduce the reliance on animals for drug testing. In this review, we have discussed the developmental and regulatory aspects of organoids and highlighted their importance in drug development. We have first summarized different types of culture-based organoid systems such as submerged Matrigel, micro-fluidic 3D cultures, inducible pluripotent stem cells, and air-liquid interface cultures. These systems help us understand the intricate interplay between cells and their surrounding milieu for identifying functions of target receptors, soluble factors, and spatial interactions. Further, we have discussed the advances in humanized severe-combined immunodeficiency mouse models and their applications in the pharmacology of immune-oncology. Since regulatory aspects are important in using organoids for drug development, we have summarized FDA and EMA regulations on organoid research to support pre-clinical studies. Finally, we have included some unique studies highlighting the use of organoids in studying infectious diseases, cancer, and fundamental biology. These studies also exemplify the latest technological advances in organoid development resulting in improved efficiency. Overall, this review comprehensively summarizes the applications of organoids in early drug development during discovery and pre-clinical studies.

PMID:39002723 | DOI:10.1016/j.xphs.2024.06.016

Int J Surg Case Rep. 2024 Jul 12;121:110032. doi: 10.1016/j.ijscr.2024.110032. Online ahead of print.

ABSTRACT

INTRODUCTION: Extrapulmonary tuberculosis is rare even in endemic areas, and is dominated by lymph node involvement. Tonsillar tuberculosis is exceptional. The clinical examination and radiological explorations are non-specific.

CASE PRESENTATION: A 45-year-old woman presented with chronic odynophagia and otalgia. Examination revealed an enlarged left palatine tonsil with an irregular surface and a firm consistency. Radiologic exploration was not specific. The patient underwent a tonsillar biopsy. Histopathology was consistent with tuberculosis and the patient was put on antitubercular drugs.

CLINICAL DISCUSSION: Tuberculosis is a global public health problem. Extrapulmonary tuberculosis is rare and mainly affects lymph nodes. Tonsillar tuberculosis is frequentely seen in individuals with immunodeficiency. Clinical features and imaging findings are non-specific. Diagnosis is based on histopathological and microbiological findings to rule out differential diagnoses especially cancer. Treatment is based on anti-tuberculosis drugs.

CONCLUSION: Our case illustrates a rare presentation of primary tuberculosis and highlights the importance of considering tuberculosis as a potential cause of tonsillitis.

PMID:39002392 | DOI:10.1016/j.ijscr.2024.110032

J Allergy Clin Immunol Pract. 2024 Jul 10:S2213-2198(24)00688-3. doi: 10.1016/j.jaip.2024.06.046. Online ahead of print.

ABSTRACT

BACKGROUND: Major Histocompatibility Complex Class II (MHC-II) deficiency, a combined immunodeficiency, results from loss of Human Leukocyte Antigen class II expression on antigen-presenting cells. Currently, hematopoietic stem cell transplantation (HSCT) stands as the sole curative approach, though factors influencing patient outcomes remain insufficiently explored.

OBJECTIVE: Our aim was to elucidate the clinical, immunological, and genetic profiles associated with MHC-II deficiency and identify prognostic indicators that affect survival rates.

METHODS: In this multicenter retrospective analysis, we gathered data from 35 patients diagnosed with MHC-II deficiency across 12 centers in Turkey. We recorded infection histories, gene mutations, immune cell subsets, and surface MHC-II expression on blood cells. We conducted survival analyses to evaluate the impact of various factors on patient outcomes.

RESULTS: Predominant symptoms observed were pneumonia (n=29, 82.9%), persistent diarrhea (n=26, 74.3%), and severe infections (n=26, 74.3%). The RFXANK gene mutation (n=9) was the most frequent, followed by mutations in RFX5 (n=8), CIITA (n=4), and RFXAP (n=2) genes. Patients with RFXANK mutations presented with later onset and diagnosis compared to those with RFX5 mutations (p=0.0008 and p=0.0006, respectively), alongside a more significant diagnostic delay (p=0.020). A notable founder effect was observed in 5 patients with a specific RFX5 mutation (c.616G>C). The overall survival rate for patients was 28.6% (n=10), showing a significantly higher proportion in individuals with HSCT (n=8, 80%). Early demise (p=0.006) and higher CD8⁺ T-cell counts were observed in patients with the RFX5 mutations compared to RFXANK-mutant patients (p=0.006 and p=0.009, respectively).

CONCLUSION: The study delineates the genetic and clinical panorama of MHC-II deficiency, emphasizing the prevalence of specific gene mutations such as RFXANK and RFX5. These insights facilitate early diagnosis and prognosis refinement, significantly contributing to the management of MHC-II deficiency.

PMID:38996837 | DOI:10.1016/j.jaip.2024.06.046

Int J Mol Sci. 2024 Jul 4;25(13):7333. doi: 10.3390/ijms25137333.

ABSTRACT

Clustered regularly interspersed short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology has revolutionized the field of gene therapy as it has enabled precise genome editing with unprecedented accuracy and efficiency, paving the way for clinical applications to treat otherwise incurable genetic disorders. Typically, precise genome editing requires the delivery of multiple components to the target cells that, depending on the editing platform used, may include messenger RNA (mRNA), protein complexes, and DNA fragments. For clinical purposes, these have to be efficiently delivered into transplantable cells, such as primary T lymphocytes or hematopoietic stem and progenitor cells that are typically sensitive to exogenous substances. This challenge has limited the broad applicability of precise gene therapy applications to those strategies for which efficient delivery methods are available. Electroporation-based methodologies have been generally applied for gene editing applications, but procedure-associated toxicity has represented a major burden. With the advent of novel and less disruptive methodologies to deliver genetic cargo to transplantable cells, it is now possible to safely and efficiently deliver multiple components for precise genome editing, thus expanding the applicability of these strategies. In this review, we describe the different delivery systems available for genome editing components, including viral and non-viral systems, highlighting their advantages, limitations, and recent clinical applications. Recent improvements to these delivery methods to achieve cell specificity represent a critical development that may enable in vivo targeting in the future and will certainly play a pivotal role in the gene therapy field.

PMID:39000440 | DOI:10.3390/ijms25137333

Cells. 2024 Jun 21;13(13):1077. doi: 10.3390/cells13131077.

ABSTRACT

James German’s work to establish the natural history and cancer risk associated with Bloom syndrome (BS) has had a strong influence on the generation of scientists and clinicians working to understand other RECQ deficiencies and heritable cancer predisposition syndromes. I summarize work by us and others below, inspired by James German’s precedents with BS, to understand and compare BS with the other heritable RECQ deficiency syndromes with a focus on Werner syndrome (WS). What we know, unanswered questions and new opportunities are discussed, as are potential ways to treat or modify WS-associated disease mechanisms and pathways.

PMID:38994931 | DOI:10.3390/cells13131077

Expert Rev Clin Immunol. 2024 Jul 12:1-12. doi: 10.1080/1744666X.2024.2368195. Online ahead of print.

ABSTRACT

BACKGROUND: Personalized medicine requires the assessment of the impact of health care interventions on Health-Related Quality of Life.

RESEARCH DESIGN AND METHODS: We run an observational study of HRQoL in 140 CVID patients with biannual assessments over 8 years using a disease-specific tool, the CVID_QoL, and the GHQ questionnaires. Factors influencing changes in HRQoL scores were identified using multiple linear regression models with a stepwise procedure.

RESULTS: Infections frequency, female gender, and chronic enteropathy were associated with worse global CVID_QoL scores. The presence of permanent organ damage and older age contributed to the perception of being at risk of health deterioration, while chronic enteropathy was associated with fatigue. The presence of permanent organ damage was also associated with perceived difficulties in usual activities. The frequency of infections was the main risk factor for difficulties in long-term planning and perceptions of vulnerability. Before COVID-19, improved HRQoL scores were associated with reduced respiratory infections and changes in immunoglobulin replacement route and setting. The COVID-19 pandemic caused a sudden deterioration in all HRQoL dimensions, and a further deterioration in the emotional dimension was observed during the pandemic period. Patients who died during the study had worse CVID_QoL scores at all time points, confirming that HRQoL performance is strongly related to patient outcome.

CONCLUSIONS: Periodic HRQoL assessments are needed to capture relevant issues that change over time in patients affected by long-term chronic conditions such CVID, possibly identifying areas of intervention.

PMID:38994591 | DOI:10.1080/1744666X.2024.2368195

Cureus. 2024 Jun 11;16(6):e62178. doi: 10.7759/cureus.62178. eCollection 2024 Jun.

ABSTRACT

Griscelli syndrome (GS) type II is a rare hereditary disorder characterized by partial albinism, immunodeficiency, and the subsequent development of hemophagocytic syndrome (HPS). Herein, we present a case involving a four-month-old infant admitted to our facility due to a prolonged fever complicated by HPS. The diagnosis of GS type 2 was established based on a constellation of clinical and laboratory findings: consanguinity, familial history of early infectious fatalities, ocular-cutaneous hypopigmentation, characteristic silvery hair sheen, onset of HPS, and notably, the pathognomonic appearance upon microscopic examination of a hair sample. The absence of giant granules within nucleated cells helped exclude Chediak-Higashi syndrome.

PMID:38993473 | PMC:PMC11239126 | DOI:10.7759/cureus.62178