Journal of cellular immunology最新文献

Using four core genotypes (FCG) mice, we have previously shown a larger number of CD4⁺ and CD8⁺ T cells in the spleens of female mice, a sex difference that develops by postnatal day 7 and is retained through adulthood. This difference in splenic T cell number is a consequence of reduced thymic egress and reduced splenic seeding in male mice, caused in part by the male-specific perinatal surge of testosterone, and in part by Sry, which is overexpressed in this model. Here, we used the background strain for FCG mice (C57BL/6J) to ask whether sex influenced actual immunity in the postnatal period. Pups were immunized on postpartum days 1 or 3 with Mycobacterium tuberculosis (Mtb), challenged on day 7 with Mtb purified protein derivative (PPD), and sacrificed on day 8. Subsequent ex vivo challenges of splenocytes showed PPD-stimulated CD8⁺ responses (increased CD8⁺, increased CD8⁺CD44^hi, decreased CD8⁺CD44^hiCD127^-/lo) but no differences between males and females. However, when CD8⁺ T cells were analyzed for IFN-γ and IL-2 production, although there was no sex difference in mono-functional IFN-γ⁺ (100%) or IL-2⁺ (67%), only females (0% of males and 42% of females) produced bi-functional (IFN-γ⁺IL-2⁺) cells. Ex vivo PPD-stimulated responses of other relevant cells from the spleen showed no sex differences in dendritic cells (CD11c⁺CD86⁺IL-6⁺) but females had more (3-fold) IL-6-producing macrophages (F4/80⁺CD86⁺IL-6⁺) and reduced T regulatory cells (CD4⁺CD25⁺Foxp3⁺). We conclude that some sex differences in immunity are evident at one week of age in Mtb immunized mouse pups, with females exhibiting qualitatively superior Mtb-specific immune responses.

Lymphangioleiomyomatosis (LAM) is a rare, female-dominated pulmonary cystic disease. Cysts that develop in LAM are characterized by the presence of smooth muscle-like (LAMCore) cells in the periphery. These cells harbor mutations in Tuberous Sclerosis Complex 1 or 2 (TSC1/2), driving uncontrolled proliferation through the mTORC1 pathway. LAMCore cells originate from an extrapulmonary source. Published data supports the uterine origin of LAMCore cells that metastasize from the uterus to precipitate pulmonary function destruction. Immune evasion is hypothesized to occur to allow seeding of the lungs from the uterus. This evasion specifically involves dysfunctional NK cells to allow aberrant proliferation and migration from the tissue. Single-cell RNA sequencing revealed changes in chemokine and cytokine protein and receptor expression in uterine NK (uNK) and other immune cell populations in a uterine-specific Tsc2-knockout mouse model of LAM. ELISA data revealed increased concentrations of multiple pro-inflammatory cytokines in the sera of aged Tsc2-knockout mice. Flow cytometry, IHC, and functional assays identified compositional and functional insufficiencies of the uNK cells in Tsc2-knockout mice. Furthermore, depletion of NK cells led to the increased development of pulmonary metastases. These data suggest an inflammatory feedback loop affecting multiple cell types including uNK cells, macrophages, and neutrophils. This leads to alterations in immune cell function and composition which allow for LAMCore cell metastasis from the uterine tissue, which may provide a novel mechanism for LAM development.

Candida auris is a multidrug-resistant fungal pathogen that presents a growing global health challenge, particularly due to its ability to cause invasive bloodstream and deep-seated infections in vulnerable patients. Monoclonal antibody (mAb)-based immunotherapy offers a novel and targeted approach to overcoming the limitations of current antifungal treatments. This commentary highlights the protective efficacy of Candida-specific mAbs, C3.1, 6H1, and 9F2, in in vivo mouse models of disseminated candidiasis. These antibodies target distinct, conserved surface antigens and significantly reduce fungal burden while improving survival outcomes. Their translational potential lies in their specificity, low toxicity, and ability to enhance host immune responses, making them strong candidates for future development as adjunct or alternative therapies for invasive fungal infections in humans.

Congenital neutropenia is characterized by a reduced neutrophil count, decreased innate immunity and increased susceptibility to recurrent infections. While congenital neutropenia has various genetic causes, recent studies have linked TCIRG1 mutations to this condition. TCIRG1, a key component of the vacuolar ATPase (V-ATPase) complex, is essential for osteoclast function, but its role in hematopoiesis remains unclear. We previously identified heterozygous TCIRG1 mutations, including R736S, R736C, R736P, and E722D, in individuals with congenital neutropenia. However, the mechanism by which these mutations lead to impaired granulopoiesis remains unknown. To investigate the functional consequences of TCIRG1 mutations, we generated induced pluripotent stem cells (iPSCs) from affected individuals and healthy controls. Using in vitro differentiation protocols, we assessed hematopoietic progenitor formation, proliferation, survival, and neutrophil differentiation. We observed significant defects in myeloid differentiation and increased cell death in patient-derived iPSC lines. CRISPR/Cas9-mediated correction of the R736C mutation restored normal neutrophil differentiation, confirming its pathogenic role. Immunofluorescence analysis revealed reduced expression and altered intracellular localization of the TCIRG1 protein, characterized by a more diffuse cytosolic distribution in the mutant cell lines. Our findings suggest that TCIRG1 mutations impair neutrophil development, likely through structural and functional disruption of the V-ATPase complex. This study provides new insights into the molecular basis of TCIRG1-associated neutropenia and highlights potential avenues for therapeutic intervention.

Introduction: Renal Cell Carcinoma (RCC) is among the most frequently diagnosed malignancies in both genders with over 81,000 estimated cases in 2024. Despite increasing incidence of renal cell carcinomas <4 cm, up to 1/3 of patients diagnosed with RCC exhibit metastatic disease (mRCC) at time of diagnosis. Cytoreductive nephrectomy (CN), a procedure which encompasses the surgical removal of the primary tumor in patients with metastatic disease, was offered upfront as standard of care during the cytokine era; however, as systemic treatment has evolved, the role of CN in mRCC patients has become less clear.

Purpose of review: We sought to review the evolution of CN in mRCC patients from historical treatments through current standard of care considering ongoing clinical trials and perioperative considerations for CN in patients treated with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI).

Conclusion: CN following immunotherapy is safe and beneficial in appropriately selected patients. The choice to perform CN in patients with mRCC amidst an ever-changing treatment landscape is nuanced. Clinical trial enrollment is critical to refine selection criteria and timing of CN. As treatment options continue to progress, shared decision-making and multidisciplinary collaboration remain paramount in selecting the optimal treatment course for each patient.

Objective: Chikungunya virus is spread by mosquitos and causes a debilitating chronic arthritis that has no standard treatment to date and no specific measures of disease activity. The objective of this expert group was to develop a measure of chikungunya arthritis that would be useful for clinical trials and patient care.

Methods: A group of rheumatologists and biostatisticians experienced in the clinical and pathological mechanisms of chikungunya evaluated component measures for inclusion in a chikungunya arthritis disease activity score (CHIK-DAS). Utilizing data from a Colombian cohort of 158 chikungunya arthritis patients, linear regression identified components that were independently associated with patient reported outcomes assessing disability, pain, physical and mental quality of life and mobility. A preliminary instrument was developed using multiple imputation and regression backward selection. Cutoffs for grading disease severity were determined.

Results: Stiffness, ankle tenderness, and a 30 tender joint count that included the 28 joints traditionally included in the Disease Activity Score-28 were selected in a regression model predicting a composite of five patient reported outcomes. A CHIK-DAS scoring formula was developed through a weighted combination of these selected variables. In comparison to the DAS-28, the CHIK-DAS had improved predictive value for a composite outcome of disability, pain, physical and mental quality of life and mobility. Disease activity cutoffs were defined for remission (<40), mild (40-49.99), moderate (50-59.99) and severe (60+) disease.

Conclusion: The CHIK-DAS is a chikungunya specific measure of disease activity that includes the DAS-28 with the addition of ankle tenderness and a stiffness item that are prominent components of chikungunya arthritis. CHIK-DAS may be used as a specific measure of disease activity in chikungunya arthritis in clinical trials and patient care. This metric needs further validation in additional cohorts.