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Nutrients. 2024 Jan 26;16(3):373. doi: 10.3390/nu16030373.

ABSTRACT

Despite substantial heterogeneity of studies, there is evidence that antibiotics commonly used in primary care influence the composition of the gastrointestinal microbiota in terms of changing their composition and/or diversity. Benzyl isothiocyanate (BITC) from the food and medicinal plant nasturtium (Tropaeolum majus) is known for its antimicrobial activity and is used for the treatment of infections of the draining urinary tract and upper respiratory tract. Against this background, we raised the question of whether a 14 d nasturtium intervention (3 g daily, N = 30 healthy females) could also impact the normal gut microbiota composition. Spot urinary BITC excretion highly correlated with a weak but significant antibacterial effect against Escherichia coli. A significant increase in human beta defensin 1 as a parameter for host defense was seen in urine and exhaled breath condensate (EBC) upon verum intervention. Pre-to-post analysis revealed that mean gut microbiome composition did not significantly differ between groups, nor did the circulating serum metabolome. On an individual level, some large changes were observed between sampling points, however. Explorative Spearman rank correlation analysis in subgroups revealed associations between gut microbiota and the circulating metabolome, as well as between changes in blood markers and bacterial gut species.

PMID:38337658 | PMC:PMC10857499 | DOI:10.3390/nu16030373

Joint Bone Spine. 2024 Feb 7:105702. doi: 10.1016/j.jbspin.2024.105702. Online ahead of print.

ABSTRACT

Chimeric Antigen Receptor T-cell therapy (CAR-T), currently employed routinely for treating B-cell malignancies, has emerged as a groundbreaking approach in addressing severe autoimmune diseases, especially for systemic lupus erythematosus (SLE). The immunological rationale for targeting B lymphocytes in autoimmune diseases is well-established, demonstrating success in numerous autoantibody-mediated autoimmune conditions through targeted therapies over several years. However, this approach has often proven ineffective in the context of systemic lupus erythematosus. Recent data on CAR-T usage in lupus, revealed promising results including rapid and prolonged remission without treatment, highlighting the potential of CAR-T therapy in severe lupus cases. This article provides a comprehensive overview of CAR-T cells, tracing their evolution from hematological malignancies to their recent applications in autoimmune disorder, especially in lupus. Clinical trials within a regulated framework are now imperative to assess the procedural aspects in order to validate the considerable promise of CAR-T cell therapy in the field of autoimmune diseases. This includes evaluating safety and long-term efficacy and security of the procedure, the benefit-risk ratio in the field of autoimmunity, the availability and cost-related issues associated with this emerging cellular therapy procedure.

PMID:38336271 | DOI:10.1016/j.jbspin.2024.105702

ACS Synth Biol. 2024 Feb 9. doi: 10.1021/acssynbio.3c00518. Online ahead of print.

ABSTRACT

Optogenetics is a versatile and powerful tool for the control and analysis of cellular signaling processes. The activation of cellular receptors by light using optogenetic switches usually requires genetic manipulation of cells. However, this considerably limits the application in primary, nonengineered cells, which is crucial for the study of physiological signaling processes and for controlling cell fate and function for therapeutic purposes. To overcome this limitation, we developed a system for the light-dependent extracellular activation of cell surface receptors of nonengineered cells termed OptoREACT (Optogenetic Receptor Activation) based on the light-dependent protein interaction of A. thaliana phytochrome B (PhyB) with PIF6. In the OptoREACT system, a PIF6-coupled antibody fragment binds the T cell receptor (TCR) of Jurkat or primary human T cells, which upon illumination is bound by clustered phytochrome B to induce receptor oligomerization and activation. For clustering of PhyB, we either used tetramerization by streptavidin or immobilized PhyB on the surface of cells to emulate the interaction of a T cell with an antigen-presenting cell. We anticipate that this extracellular optogenetic approach will be applicable for the light-controlled activation of further cell surface receptors in primary, nonengineered cells for versatile applications in fundamental and applied research.

PMID:38335541 | DOI:10.1021/acssynbio.3c00518

Cells. 2024 Jan 26;13(3):238. doi: 10.3390/cells13030238.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities.

METHODS: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines.

RESULTS: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression.

CONCLUSION: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.

PMID:38334630 | PMC:PMC10854834 | DOI:10.3390/cells13030238

Cells. 2024 Jan 23;13(3):212. doi: 10.3390/cells13030212.

ABSTRACT

Integrin receptors are heterodimeric surface receptors that play multiple roles regarding cell-cell communication, signaling, and migration. The four members of the β₂ integrin subfamily are composed of an alternative α (CD11a-d) subunit, which determines the specific receptor properties, and a constant β (CD18) subunit. This review aims to present insight into the multiple immunological roles of integrin receptors, with a focus on β₂ integrins that are specifically expressed by leukocytes. The pathophysiological role of β₂ integrins is confirmed by the drastic phenotype of patients suffering from leukocyte adhesion deficiencies, most often resulting in severe recurrent infections and, at the same time, a predisposition for autoimmune diseases. So far, studies on the role of β₂ integrins in vivo employed mice with a constitutive knockout of all β₂ integrins or either family member, respectively, which complicated the differentiation between the direct and indirect effects of β₂ integrin deficiency for distinct cell types. The recent generation and characterization of transgenic mice with a cell-type-specific knockdown of β₂ integrins by our group has enabled the dissection of cell-specific roles of β₂ integrins. Further, integrin receptors have been recognized as target receptors for the treatment of inflammatory diseases as well as tumor therapy. However, whereas both agonistic and antagonistic agents yielded beneficial effects in animal models, the success of clinical trials was limited in most cases and was associated with unwanted side effects. This unfavorable outcome is most probably related to the systemic effects of the used compounds on all leukocytes, thereby emphasizing the need to develop formulations that target distinct types of leukocytes to modulate β₂ integrin activity for therapeutic applications.

PMID:38334604 | PMC:PMC10854705 | DOI:10.3390/cells13030212

Ann Med Surg (Lond). 2024 Jan 3;86(2):1205-1209. doi: 10.1097/MS9.0000000000001670. eCollection 2024 Feb.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by elevated serum IgE levels, recurrent infections, and various clinical features. Early diagnosis, prompt management of infections, and supportive care are essential in improving outcomes for individuals with HIES. Genetic testing, including STAT3 gene sequencing, plays a crucial role in confirming the diagnosis. Further research is needed to enhance our understanding of HIES and develop targeted therapies to improve the quality of life for affected individuals.

CASE PRESENTATION: This case report presents the clinical features and management of a 37-year-old male with HIES, diagnosed at the age of 2 due to recurrent cold abscesses caused by Staphylococcal infections.

CLINICAL DISCUSSION: The patient exhibited typical symptoms of HIES, including recurrent eczema, frequent bacterial infections, mucocutaneous candidiasis, and various physical abnormalities. Diagnostic markers such as elevated IgE levels and eosinophilia supported the HIES diagnosis, which was further confirmed by the identification of a STAT3 gene mutation. Treatment primarily involved supportive measures and antibiotics for infections. The patient’s blood test results and imaging findings revealed abnormalities such as low red blood cell count, elevated erythrocyte sedimentation rate, and pulmonary nodules.

CONCLUSION: This case report highlights the importance of early diagnosis, prompt management of infections, and the need for ongoing research to improve our understanding and treatment of HIES.

PMID:38333292 | PMC:PMC10849427 | DOI:10.1097/MS9.0000000000001670

Semin Arthritis Rheum. 2024 Jan 17;65:152387. doi: 10.1016/j.semarthrit.2024.152387. Online ahead of print.

ABSTRACT

Primary immunodeficiency Disorders (PIDS) are rare, mostly monogenetic conditions which can present to a number of specialties. Although infections predominate in most PIDs, some individuals can manifest autoimmune or inflammatory sequelae as their initial clinical presentation. Identifying patients with PIDs can be challenging, as some can present later in life. This is often seen in patients with Common Variable Immunodeficiency Disorders (CVID), where symptoms can begin in the sixth or even seventh decades of life. Some patients with PIDs including CVID can initially present to rheumatologists with autoimmune musculoskeletal manifestations. It is imperative for these patients to be identified promptly as immunosuppression could lead to life-threatening opportunistic infections in these immunocompromised individuals. These risks could be mitigated by prior treatment with subcutaneous or intravenous (SCIG/IVIG) immunoglobulin replacement or prophylactic antibiotics. Importantly, many of these disorders have an underlying genetic defect. Individualized treatments may be available for the specific mutation, which may obviate or mitigate the need for hazardous broad-spectrum immunosuppression. Identification of the genetic defect has profound implications not only for the patient but also for affected family members, who may be at risk of symptomatic disease following an environmental trigger such as a viral infection. Finally, there may be clinical clues to the underlying PID, such as recurrent infections, the early presentation of severe or multiple autoimmune disorders, as well as a relevant family history. Early referral to a clinical immunologist will facilitate appropriate diagnostic evaluation and institution of treatment such as SCIG/IVIG immunoglobulin replacement. This review comprises three sections; an overview of PIDs, focusing on CVID, secondly genetic testing of PIDs and finally the clinical presentation of these disorders to rheumatologists.

PMID:38330740 | DOI:10.1016/j.semarthrit.2024.152387

Open Forum Infect Dis. 2024 Jan 17;11(2):ofad678. doi: 10.1093/ofid/ofad678. eCollection 2024 Feb.

ABSTRACT

Patients with severe primary immunodeficiency are at risk for complications from live-attenuated vaccines. Here, we report a case of a vaccine-associated paralytic polio and Bacille Calmette-Guérin disease in a 6-month-old girl with severe combined immunodeficiency resulting from homozygous recombinant activating gene 1 deficiency. The patient was successfully treated with intravenous immunoglobulins and oral pocapavir for poliovirus, and antimycobacterial therapy for regional Bacille Calmette-Guérin disease, allowing stem cell transplant. Following transplantation, poliovirus type 3 with 13 mutations was detected from cerebrospinal fluid but not from stool, indicating ongoing viral evolution in the central nervous system despite pocapavir treatment. Clinical improvement and immune reconstitution allowed the patient to be successfully discharged with no further detection of poliovirus.

PMID:38328499 | PMC:PMC10849832 | DOI:10.1093/ofid/ofad678

Clin Immunol. 2024 Feb 5;260:109922. doi: 10.1016/j.clim.2024.109922. Online ahead of print.

ABSTRACT

IKAROS, encoded by IKZF1, is a tumor suppressor and a key hematopoietic transcription factor responsible for lymphoid and myeloid differentiation. IKZF1 mutations result in inborn errors of immunity presenting with increased susceptibility to infections, immune dysregulation, and malignancies. In particular, patients carrying IKZF1 gain-of-function (GOF) mutations mostly exhibit symptoms of immune dysregulation and polyclonal plasma cell proliferation. Herein, we describe seven new IKAROS GOF cases from two unrelated families, presenting with novel infectious, immune dysregulation and hematologic diseases. Two of the patients underwent allogeneic hematopoietic cell transplantation (HCT) due to poorly responsive complications. HCT was well-tolerated achieving full engraftment in both patients receiving reduced intensity, matched unrelated donor grafts, with no severe acute or chronic graft-vs-host-disease, and in remission from their diseases 2.5 and 4 years post-HCT, respectively. These results suggest that HCT is a valid and curative option in patients with IKAROS GOF disease and severe clinical manifestations.

PMID:38320737 | DOI:10.1016/j.clim.2024.109922

Front Immunol. 2024 Jan 22;15:1339421. doi: 10.3389/fimmu.2024.1339421. eCollection 2024.

ABSTRACT

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency is a rare genetic condition that causes recurrent swelling with consequent functional impairment and decreased quality of life. Long-term prophylaxis (LTP) to prevent angioedema episodes is a key component of disease management. Berotralstat, an oral, once-daily plasma kallikrein inhibitor, was approved for LTP by Health Canada in 2022.

METHODS: We conducted a retrospective, real-world study investigating the effectiveness and adverse effects of berotralstat. Data on angioedema frequency, disease control, and adverse events were tabulated. Patient satisfaction with treatment was scored on a 5-point Likert scale, with 1 representing very unsatisfied and 5 representing very satisfied with therapy.

RESULTS: From June, 2022 and May, 2023, 8 patients with HAE type 1 or type 2 received berotralstat. Effectiveness data were available for 7 patients who continued the drug for at least 3 months, 4 of whom switched to berotralstat from plasma-derived C1 inhibitor LTP. In these 7 patients, the average number of attacks per month decreased from 3.3 to 1.6 (p<0.05), representing a ~52% reduction in attack frequency. Median angioedema control test score numerically improved from 8 to 13 (p=0.0781). Of the 8 patients who received berotralstat, 3 reported no adverse effects and 5 experienced gastrointestinal side effects, which were mild and transient in 3 and led to discontinuation in 1. Average treatment satisfaction was between satisfied and very satisfied at 4.3.

CONCLUSION: Berotralstat is an effective agent for long-term prophylaxis in HAE. Most patients experienced no adverse effects or mild, transient gastrointestinal symptoms.

PMID:38318176 | PMC:PMC10839047 | DOI:10.3389/fimmu.2024.1339421