Journal of Clinical Immunology最新文献

Purpose: The Ezrin-Radixin-Moesin (ERM) family member moesin (MSN) plays a crucial role in reversibly linking F-actin to the cell membrane. Patients carrying MSN gene mutations consistently exhibit immunodeficiencies. However, due to the scarce number of reported cases worldwide, the mechanism by which MSN mutation leads to immune function defects remains unclear. This study aims to profile the immunological features in MSN mutant patients elaborately.

Methods: In this article, we present a case study of a patient with c.511 C > T, p.Arg171Trp (p.R171W) mutation on the MSN gene. We analyzed abnormalities in peripheral immune cell subsets by quantitative analysis, morphological examination, and functional molecule assessment during various infection states. Using total internal reflection fluorescence microscopy (TIRFm), we visualized BCR clusters and F-actin dynamics in B cells, revealing valuable insights into B cell activation and the link between F-actin aggregation and BCR signaling in MSN mutant patients.

Results: The results suggest that the MSN c.511 C > T, p.Arg171Trp (p.R171W) mutation affects the proliferation, differentiation, metabolism, and adhesion functions in peripheral immune cells, as well as the maturation process in bone marrow cells. Additionally, we elucidate the impact of MSN mutation on B cell and T cell metabolism and propose a potential diagnostic indicator for patients with MSN gene mutations.

Conclusion: Our findings support the diagnosis of primary immunodeficiency and provide detailed insights into changes occurring in immune cells, especially B cells. Overall, our study adds to the diagnosis and pathogenesis of X-linked moesin-associated immunodeficiency (X-MAID).

The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infections due to the absence or dysfunction of T and NK cells, and nonfunctional B cells. Missense variants in the γc extracellular region are linked to atypical X-SCID with normal counts of T, B, and NK cells and less severe symptoms, yet the underlying cellular and molecular mechanisms are not well understood. This study describes a case of atypical X-SCID with a missense variant (c.420 A > T, p.R140S) in the γc extracellular domain, associated with recurrent bacterial, fungal, and viral infections. We found that the R140S variant leads to reduced surface expression and variably affects cytokine receptor signaling. Specifically, STAT5 phosphorylation and proliferation in CD4⁺ T and CD8⁺ T cells are impaired in response to IL-7, a cytokine essential for T cell survival, proliferation and function. Notably, γc^R140S predominantly localizes to the endoplasmic reticulum, in contrast to WT γc, which is found in acidic compartments. Despite this mislocalization, γc^R140S does not trigger unfolded protein responses, and its protein stability and degradation pathways remain unaffected. Nevertheless, cells expressing high levels of γc^R140S exhibited a competitive disadvantage in culture compared to those expressing WT γc, resulting in the enrichment of cells expressing lower levels of γc^R140S. These findings extend our understanding of how mutations in the extracellular domain of γc can lead to reduced protein expression and influence the pathophysiology of atypical X-SCID.

Purpose: Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in ACTB, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of ACTB mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel ACTB variant in a patient with BRWS1.

Methods: Whole-exome sequencing identified a heterozygous ACTB p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant ACTB constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated.

Results: The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation.

Conclusion: BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.

Background and objectives: Germline pathogenic variants in the mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) encodes a caspase-like protease that plays a crucial role in the caspase recruitment domain (CARD)-B-cell lymphoma 10 (BCL10)-MALT1 (CBM) complex. This complex mediates the activation of nuclear factor-kB (NF-kB) pathway and are associated with diverse human diseases including combine immunodeficiency (CID), lymphoproliferation and others. This study aimed to determine the underlying cause of immune deficiency and immune dysregulation in a patient presented with recurrent respiratory infections, aphthous ulcers, dermatitis, chronic diarrhea, failure to thrive and early death.

Methods: Clinical and laboratory records were reviewed. Patients underwent next-generation sequencing (NGS), and analysis of genomic DNA was performed on the patient and her parents. Lymphocyte subsets, MALT1 expression and NF-kB signaling was evaluated by flow cytometry, RT-PCR and immunoblotting.

Results: The patient carried a novel pathogenic biallelic loss-of-function variant in MALT1 (c.1411G > A; p.D471N) located in the caspase-like domain, leading to severely reduced MALT1 protein expression. Impaired CBM-mediated NF-κB activation was confirmed by reduced phosphorylation of the p65 subunit, resulting in deficient production of IL-2 and TNF-α. This functional defect caused lower Tfr and Treg cells, a normal proportion of Tfh cells, with higher expression of activation markers PD-1 and ICOS. The patient displayed low NK cell and B cell counts, together with a developmental block at the transitional B cell stage. Additionally, the proportion of marginal zone-like B cells (MZB-like) was markedly decreased, indicating impaired B cell differentiation.

Conclusions: Human MALT1 deficiency causes profound CID by impairing CBM-mediated NF-kB signaling and MALT1-paracaspase activity. Consistent with the reported variants located in the caspase-like domain, our patient presented with an inflammatory phenotype, supporting the notion that the MALT1 D471N mutation phenocopies a partial loss of both MALT1 scaffolding function and paracaspase activity. Prompt hematopoietic stem cell transplantation (HSCT) is highly recommended as an effective therapy for MALT1 deficiency.

Natural Killer (NK) cells naturally recognize and eliminate leukemic cells. However, the molecular interactions that govern these responses are diverse due to the large number of activating and inhibitory NK receptors that modulate NK functions and the diversity of corresponding ligands that are differentially expressed in acute lymphoblastic and myeloblastic leukemias. We identified resting NKG2A⁺ NK cells and NKG2A⁺KIR⁺ NK cell subsets as the most effective in eliminating lymphoid and myeloid leukemic cells respectively. The NKG2A⁺KIR^±CD57^- cell subsets show high expression of activating receptors and a functional transcriptomic profile, but differ in KIR2DL5 expression. The frequency of KIR2DL5⁺ NK cells increases with the number of expressed KIR. Furthermore, KIR2DL5 is preferentially co-expressed with KIR2DL1 and is negatively regulated by NKG2A. Of note, CD57 expression, regardless of the NK cell subset considered, is associated with reduced receptor expression, consistent with its reduced cytotoxic potential. Furthermore, molecular interactions between NK cells and leukemic cells influence NK cell responses, particularly the inhibitory KIR2DL5-PVR axis. The integration of these data is of importance for the optimization of NK cell-based immunotherapies, as the selection of NK cell donors represents a key parameter for the improvement of these therapies.

Background: The CD247 chain of the T-cell receptor (TCR) is essential for normal T cell development and function. Reported CD247-deficient patients showed severe immunodeficiency despite the presence of two populations of peripheral T cells, most with low TCR levels carrying the germline variant and a few with higher TCR levels due to somatic reversion. However, the revertant T cells remained a minority and did not improve the patients' clinical status.

Purpose: To compare the capability of somatic revertant variants of CD247 germline changes (p.M1T and p.Q70X) to restore TCR expression and function.

Methods: CD247 wild-type (WT) and p.Q70L/W/Y somatic variants were individually introduced in CD247-deficient mouse (MA5.8), human mutant (PM1T), and CRISPR/Cas9-generated Jurkat (ZKO) T cell lines by nucleofection or transduction.

Results: MA5.8 mouse T cells do not accurately model human CD247 deficiencies, as Q70X restores TCR expression in MA5.8 but not in human cells. In human cell models, all somatic revertant variants restored TCR expression with varying degrees (WT = Q70L > Q70W > Q70Y). In contrast, TCR-induced activation events, such as CD69/CD25 upregulation, showed a different hierarchy (WT = Q70W > Q70L = Q70Y). Furthermore, all CD247 somatic variants failed to induce TCR-mediated ZAP70 tyrosine phosphorylation compared to WT.

Conclusion: Somatic reversions, such as those detected in patients with pathogenic CD247 germinal changes, display a discordant capability to rescue TCR expression versus function. These findings shed light on the role of CD247 in TCR expression and function during human T cell development, with implications for immunodeficiencies, as well as for the biological consequences of CD247 somatic mosaicism.

Background: The assessment of polysaccharide responsiveness via vaccination is pivotal in the evaluation of patients for primary immunodeficiency. However, the applicability of current guidelines provided by the American Academy of Allergy, Asthma & Immunology (AAAAI) has been subject to scrutiny.

Methods: We conducted a prospective study involving 120 healthy Danish adult blood donors. Antibodies targeting pneumococcal capsular polysaccharide serotypes were quantified using a multianalyte bead immunoassay before and four to eight weeks post-vaccination. Polysaccharide responsiveness in donors was assessed according to AAAAI guidelines.

Results: Remarkably, only a minority of participants (2.5%) demonstrated a normal polysaccharide response per AAAAI criteria. This finding prompted us to advocate for an alternative approach based on percentile rankings relative to a reference population. Polysaccharide Responsiveness Percentile (PRP) was not significantly associated with age, sex, vaccine batch, or the duration between vaccination and antibody measurements in our cohort supporting its robustness, generalizability, and potential for standardized clinical application.

Conclusion: Our study unveils significant limitations of the AAAAI guidelines, highlighting the imperative for a more robust and adaptable approach. By introducing a novel PRP assessment method, we aim to enhance the accuracy and reliability of immune function evaluations.

Purpose: Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare vasculitis characterized by increased eosinophils in human tissues and peripheral blood. In this case, we present a 53-year-old female patient with EGPA. By this case and literature review, we want to explain the early manifestations, diagnosis, and management of EGPA, which will help clinicians to understand the disease and attach importance to the possibility of dupilumab-induced EGPA, to improve the early diagnosis rate of EGPA, and reduce misdiagnosis and missed diagnosis.

Methods: The diagnostic criteria for EGPA established by the American Rheumatology Association (ACR) in 2022 were used; these criteria encompass clinical presentation, laboratory tests, and pathological biopsy. In addition, we conducted a comprehensive literature review on this case.

Result: We present a 53-year-old female patient who developed severe peripheral neuropathic pain after the administration of dupilumab for the treatment of refractory asthma and sinusitis. The patient's symptoms, laboratory examination findings, and nasopharyngeal biopsy pathology results collectively support the diagnosis of EGPA. When dupilumab was converted to mepolizumab combined with glucocorticoid, her peripheral neuropathic pain and asthma symptoms were dramatically relieved. Our literature review also provides a detailed discussion on the relationship between Dupilumab and EGPA.

Conclusion: We present a case of EGPA with peripheral neuropathic pain induced by Dupilumab, and mepolizumab has a good therapeutic effect on this patient. Our literature review shows that although dupilumab is effective in treating eosinophilic airway inflammatory diseases, clinicians must pay attention to the possibility of dupilumab inducing or aggravating EGPAs.