Journal of Clinical Immunology最新文献

Familial Mediterranean Fever (FMF) is caused by mutations in the MEFV gene, which encodes for pyrin. Although genetic testing is commonly employed for FMF diagnosis, the interpretation of genetic results is often challenging. Therefore, we aimed to functionally characterise the p.R202Q MEFV alteration. Furthermore, we hypothesized that inflammation may affect genomic stability and neutrophilic (N) subsets. A cohort comprising patients with FMF (n = 4), p.R202Q variant (n = 18) and FMF-like (n = 8) were selected from the Outpatient Clinic for Autoinflammatory diseases of Padova University Hospital. Primary monocytes were incubated for 3 h in the presence of LPS or LPS + PKN1/2 inhibitor (UCN-01). Colchicine pretreatment was applied to assess its anti-inflammatory effect. Pro-inflammatory cytokines were measured by ELISA and leukocytes were examined using May-Grünwald-Giemsa staining on blood smears. We did not find significant differences in IL-1 and IL-18 levels in monocytes treated with LPS + UCN-01 between p.R202Q patients and healthy donors (HDs). The levels of IL-1β released from LPS-stimulated patients were higher in p.R202Q patients than in HDs. We found that immature and hypersegmented neutrophils were higher in p.R202Q patients than in HD. Nuclear abnormalities were higher in FMF and p.R202Q patients than in HD. Finally, we found a higher cell rate in leukocytes from p.R202Q patients than in HDs. The p.R202Q variant did not appear to affect pyrin function, albeit these patients presented cytological alterations similar to those observed in FMF patients. These changes may contribute to FMF pathophysiology by influencing inflammation progression.

Background: DiGeorge Syndrome (DGS), a microdeletion syndrome, shows a broad spectrum from mild T-cell lymphopenia to severe combined immunodeficiency.

Aim: To define the clinical/immunophenotypical biomarkers for DGS.

Patients and methods: A total of 72 patients with 22q11.2 deletion(n = 66) and those fulfilling the DGS criteria without deletion (n = 6) were enrolled.

Results: The male/female ratio was 41/31. Median age at clinical diagnosis was 1.7 years (0 days-22 years) with follow-up for 21.7 months (0 days-17.3 years). Common evaluation reasons were cardiac features (30.6%), failure to thrive (15.3%), and neurological features (15.3%). Craniofacial dysmorphism (64/66, 97%), central nervous system findings (62/72, 86.1%), and congenital cardiovascular defect (43/70, 61.4%) were common. We noted lymphopenia (30/72, 41.7%) and low IgM (25/69, 36.2%). T helper cell counts were low in 49.3% (33/67). T cytotoxic and NK cell counts were normal/high in 80.6% (54/67) and 97% (65/67) of patients, respectively. 42.3% (11/26) had low CD4 + TEMRA, and 34.6% (9/26) had low CD8 + TEM percentages. None had low CD8 + TEMRA. B cells were normal/high (52/67, 77.6%). 30.8%(8/26) had low switched-memory and 38.5% (10/26) had low active B cell percentages. Low IgA levels were associated with decreased lymphocyte activation and recent thymic emigrant (RTE) cell percentages. Six(8.3%) patients with lymphopenia, three of whom had congenital athymia, died.

Conclusion: CD4 lymphopenia was more common than CD8 lymphopenia. Normal/high CD8 + and NK cell counts were remarkable. Increased CD8+ TEMRA cells seem to indicate peripheral homeostatic proliferation following viral infections. Low serum IgA correlated with low RTE% and impaired T-cell function. DGS severity markers include hypocalcemia, congenital cardiac anomaly, and T-cell lymphopenia.

TLR7, which encodes a key receptor for single-stranded RNA (ssRNA) virus of the innate immune system, was recently associated with X-linked immunodeficiency and COVID-19 susceptibility. This study investigates the association between TLR7 variants and susceptibility to severe COVID-19 in a multicentric Spanish cohort. The TLR7 gene was sequenced in a cohort of 365 COVID-19 patients, stratified into two groups: one comprising mild and asymptomatic patients, considered as controls (n = 87), and the other consisting of moderate to severely affected patients hospitalized due to COVID-19 pneumonia, considered as cases (n = 278). A total of 152 unique TLR7 variants were identified, of note, six rare variants were identified in 11 cases (3.96%), all of whom belonged to the case group. The functional impact of rare TLR7 variants was assessed using a luciferase reporter assay and revealed that N215S is a loss-of-function (LOF) variant, while D332G exhibits an hypomorphic behavior. Conversely, H90Y, V219I, A448V, and R902K maintained normal signaling. No skewed X-inactivation was observed in female carriers of N215S or D332G. In addition, the common variants Q11L (rs179008), c.4-151A>G (rs179009) and c.*881C>G (rs3853839) were associated with severe pneumonia, while c.4-151A>G (rs179009) was specifically linked to Intensive Care Unit (ICU) admission. These findings highlight the role of TLR7 in antiviral immune response and its association with severe COVID-19 in men. The luciferase assay proves to be a reliable tool for evaluating TLR7 signaling, effectively distinguishing between neutral, LOF, and gain-of-function (GOF) variants. Further research is needed to better understand TLR7 variants and its implications in immunodeficiency and immune dysregulation.

A man living with HIV was found to lack expression of CD16A on his natural killer (NK) cells and monocytes. Genetic analysis revealed compound heterozygous deletion of FCGR3A, the gene encoding CD16A. The case's NK cells showed: (a) no antibody-dependent cell-mediated cytotoxicity and very low spontaneous cytotoxicity; (b) an immature phenotype marked by high expression of CD94, CD2, NKG2A, and NKG2D, and low expression of KIR2DL2 and CD57; (c) no expression of KIR3DL1 and very low expression of FcRγ; and (d) normal cytokine production. The case's monocytes and DCs were similar phenotypically and functionally to those from the donors matched for HIV status, age, and percentage of NK cells in the peripheral blood. In contrast to previously reported people with CD16A deficiency, this man did not have a history of severe infections with herpes viruses, suggesting that other immune cells and/or immunoregulatory function of NK cells may compensate for deficiency of cytolytic NK cells.

Purpose: There are few reports of renal involvement in Common Variable Immunodeficiencies (CVID) and, when present, is due to infections, inflammation, or treatments. The aim of this study was evaluating the prevalence of chronic kidney disease (CKD) and to identify CVID-related clinical, laboratory and therapeutic features inducing it.

Methods: A multicenter observational retrospective study on 367 adult CVID patients from five Italian Referral Centers for Primary Immunodeficiency.

Results: CKD was identified in 23 (6.27%) patients that were older (p < 0.001), had arterial hypertension (p < 0.001), diabetes (p = 0.002), dyslipidemia (p = 0.002), presented different ultrasound abnormalities (p < 0.001) and received predominantly intravenous immunoglobulins (IVIG) (p = 0.016). Regarding CVID infectious and non-infectious manifestations, CKD patients presented a higher frequency of COPD (p = 0.008). In the CKD group, the median absolute count of total lymphocytes (p = 0.015), the percentage of total B (p = 0.028) and transitional B cells (p = 0.008) were lower. By binomial logistic regression analysis adjusted for age, CKD patients tend to develop autoimmune cytopenia, had lower B cells percentage, increased Neutrophil-to-lymphocyte ratio and received more frequently trimethoprim-sulfamethoxazole antibiotic prophylaxis. By multivariate analysis, only autoimmune cytopenia was independently associated with CKD.

Conclusion: The prevalence of CKD in CVID is due to aging, age-related comorbidities, disease-related immune dysregulation and inflammation. Our results suggest evaluating renal function in all CVID patients, and mostly in those with a higher "inflammatory" burden.