Research

Iran Biomed J. 2024 Jun 29. doi: 10.61186/ibj.4177. Online ahead of print.

ABSTRACT

BACKGROUND: Cutaneous leishmaniasis is a major health problem caused by an intracellular pathogen of the genus Leishmania. CL results in morphologically distinct skin injuries, ranging from nodules to plaques and ulcers, which persist as a recuperating incessant injury depending on the type of contaminating parasite. There is still no effective treatment to reduce the skin lesions in patients infected with CL. The aim of this study was to develop strategies to treat skin lesions in CL patients.

METHODS: We retrieved the transcriptomic data of skin lesions from patients with CL and normal skin from the GEO database. The PPIN was constructed using the STRING database and Cytoscape v3.10.1 software. Critical genes were identified by topological network analysis and cluster detection. Finally, gene ontology and repurposing drugs for critical genes were determined.

RESULTS: CD8A, IFNG, IL-6, PTPRC, CCR7, TLR2, GSTA5, CYBB, IL-12RB2, ITGB2, FCGR3A, CTLA4, and IFNG were identified as the critical genes in PPIN and subnetworks. Enrichment analysis revealed that T-cell receptor signaling, TLR signaling, cytokine-cytokine receptor interaction, graft-versus-host disease, leishmaniasis, chemokine signaling, primary immunodeficiency, and Th17 cell differentiation were the major pathways associated with critical genes. The drug repurposing results identified cyclosporine, rituximab, infliximab, blinatumomab, and methylprednisolone as candidates for treatment of CL.

CONCLUSION: After validating our model with available experimental data, we found that critical molecules and drug candidates play a crucial role in the treatment of skin lesions caused by Leishmania in prospective studies.

PMID:39036455 | DOI:10.61186/ibj.4177

Kidney Int. 2024 Aug;106(2):320. doi: 10.1016/j.kint.2024.03.008.

NO ABSTRACT

PMID:39032971 | DOI:10.1016/j.kint.2024.03.008

Retin Cases Brief Rep. 2024 Jul 19. doi: 10.1097/ICB.0000000000001632. Online ahead of print.

ABSTRACT

PURPOSE: To report on a rare case of intermediate uveitis occurring in a patient with common variable immunodeficiency (CVID) and a heterozygous TNFRSF13B variant.

METHODS: Observational case report.

RESULTS: A 23-year-old male presented with a 3-month history of increasing floaters and blurred vision to both eyes. He had been treated with topical and intravitreal corticosteroids by his local ophthalmologist nine months before. Ocular examination demonstrated bilateral intermediate uveitis with retinal vasculitis. He had been treated with intravenous immunoglobulins during childhood, due to primary humoral immunodeficiency. Systemic work-up for other causes of intermediate uveitis was unremarkable, notably no features of systemic sarcoid-like disease were detected. Initial treatment with mycophenolate mofetil showed insufficient response, and upon switching to adalimumab, clinical remission was achieved. Immunocytometry and genetic work-up revealed a smB+CD21norm subtype of CVID and a heterozygous TNFRSF13B variant.

CONCLUSION: This report of CVID-associated intermediate uveitis in a patient with a heterozygous TNFRSF13B variant highlights the potential involvement of the eye within CVID-associated autoimmunity and the role for anti-TNF blockade in this challenging group of patients.

PMID:39029109 | DOI:10.1097/ICB.0000000000001632

Blood Adv. 2024 Jul 19:bloodadvances.2024013301. doi: 10.1182/bloodadvances.2024013301. Online ahead of print.

ABSTRACT

WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in the c-terminus of the gene CXCR4. These CXCR4 variants display impaired receptor trafficking with persistence of the CXCR4 receptor on the surface resulting in hyperactive downstream signaling following CXCL12 stimulation. In turn, this results in defective lymphoid differentiation, and reduced blood neutrophil and lymphocyte numbers. Here we report a CXCR4 mutation that in two members of a kindred, led to life-long autoimmunity and lymphoid hypertrophy as the primary clinical manifestations of WHIM syndrome. We examine the functional effects of this mutation, and how these have affected phosphorylation, activation, and receptor internalization.

PMID:39028950 | DOI:10.1182/bloodadvances.2024013301

Front Immunol. 2024 Jul 4;15:1402139. doi: 10.3389/fimmu.2024.1402139. eCollection 2024.

ABSTRACT

Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.

PMID:39026677 | PMC:PMC11254771 | DOI:10.3389/fimmu.2024.1402139

Clin Immunol. 2024 Jul 16:110320. doi: 10.1016/j.clim.2024.110320. Online ahead of print.

ABSTRACT

Vaccine challenge responses are an integral component in the diagnostic evaluation of patients with primary antibody deficiency, including Common Variable Immunodeficiency Disorders (CVID). There are no studies of vaccine challenge responses in primary hypogammaglobulinemia patients not accepted for subcutaneous/intravenous immunoglobulin (SCIG/IVIG) replacement compared to those accepted for such treatment. Vaccine challenge responses in patients enrolled in two long-term prospective cohorts, the New Zealand Hypogammaglobulinemia Study (NZHS) and the New Zealand CVID study (NZCS), were compared in this analysis. Almost all patients in the more severely affected SCIG/IVIG treatment group achieved protective antibody levels to tetanus toxoid and H. influenzae type B (HIB). Although there was a highly significant statistical difference in vaccine responses to HIB, tetanus and diphtheria toxoids, there was substantial overlap in both groups. In contrast, there was no significant difference in Pneumococcal Polysaccharide antibody responses to Pneumovax® (PPV23). This analysis illustrates the limitations of evaluating vaccine challenge responses in patients with primary hypogammaglobulinemia to establish the diagnosis of CVID and making decisions to treat with SCIG/IVIG. The conclusion from this study is that patients with symptoms attributable to primary hypogammaglobulinemia with reduced IgG should not be denied SCIG/IVIG if they have normal vaccine responses.

PMID:39025346 | DOI:10.1016/j.clim.2024.110320

Crit Care. 2024 Jul 16;28(1):243. doi: 10.1186/s13054-024-05029-4.

ABSTRACT

BACKGROUND: Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population.

METHODS: We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality.

RESULTS: We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 10⁹/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05-5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04-1.35), and older age (OR 1.04; 95% CI 1.01-1.07).

CONCLUSIONS: Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

PMID:39014504 | DOI:10.1186/s13054-024-05029-4

BMC Immunol. 2024 Jul 16;25(1):45. doi: 10.1186/s12865-024-00640-0.

ABSTRACT

INTRODUCTION: Interstitial lung disease (ILD) is a prevalent complication in patients with common variable immunodeficiency (CVID) and is often related to other characteristics such as bronchiectasis and autoimmunity. Because the term ILD encompasses a variety of acute and chronic pulmonary conditions, diagnosis is usually based on imaging features. Histopathology is less available. This study was conducted with the aim of investigating the ILD in patients with CVID.

MATERIALS AND METHODS: In this retrospective cross-sectional study, sixty CVID patients who referred to the pulmonology and immunodeficiency clinics of Mofid Children’s Hospital between 2013 and 2022 were included. The diagnosis of ILD were based on transbronchial lung biopsy (TBB) or clinical and radiological symptoms. The prevalence of ILD in CVID patients was determined. Also, the CVID patients with and without ILD were compared in terms of demographic characteristics, clinical, laboratory and radiologic findings.

RESULTS: Among all patients, ten patients had ILD (16.6%). In terms of laboratory parameters, there was a significant difference between platelets in the two groups of CVID patients with and without ILD, and the level of platelets was higher in the group of patients with ILD. Moreover, in terms of clinical symptoms, pneumonia, diarrhea and hepatomegaly were significantly different between the two groups and were statistically higher in the group of patients with ILD (P < 0.05). Autoimmunity and malignancy were not significantly different in two groups. There was a significant difference in, hyperinflation between the two groups of CVID patients with and without ILD, and the frequency of, hyperinflation was higher in the patients without ILD (P = 0.040).

CONCLUSION: Understanding the pathogenesis of ILD plays an essential role in revealing non-infectious pulmonary complications that occur in CVID patients. Increasing efforts to understand ILD not only shed light on its hidden pathogenesis and clinical features, but also enhance our understanding of CVID in a broader sense.

PMID:39014337 | DOI:10.1186/s12865-024-00640-0

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

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