Immune-mediated Research Articles

Liver cirrhosis is a risk-factor for Pneumocystis jirovecii associated mortality.

Pneumocystis jirovecci pneumonia (PCP) is a life threating disease in immunodeficient patients. Liver cirrhosis itself can lead to immunodefiency, however little is known if Pneumocystis jirovecci infection affects the outcome of patients with liver cirrhosis. We aimed to assess the predictors for Pneumocystis jirovecci-associated mortality in patients with Pneumocystis jirovecci infection treated at intensive care units. A total of 151 patients hospitalized between January 2013 and November 2019 with a PCR-confirmed Pneumocystis jirovecci infection were retrospectively included in this study and analysed for clinical predictors for PCJ associated mortality. The overall mortality in our patient cohort was 60%. Out of 151 patients included in the analysis, 67 (44%) patients suffered from liver cirrhosis. Patients with an advanced liver cirrhosis (Child-Pugh class C) showed the highest mortality rate of 84.7%. The presence of a liver cirrhosis was associated with a significant increased risk of mortality (OR: 4.809) ([95%-CI: 2.32-9.97]; p < 0.001). There was a significant correlation of Meld score and mortality (r = 0.612, p < 0.001). To our knowledge, this study represents the largest evaluation of Pneumocystis jirovecci infection in patients with advanced liver cirrhosis. Cirrhosis associated immune dysfunction (CAID) describes the spectrum of immunological disturbances in patients with cirrhosis, which is linked to a heightened vulnerability to bacterial infections. Our data indicate a heightened susceptibility to fungal infections. Understanding the phenotypic manifestations of CAID could lead to immune-targeted therapies aimed at reducing infection susceptibility and decreasing CAID-associated mortality in cirrhosis patients.

Invasive Fungal Infections in Immunocompromised Conditions: Emphasis on COVID-19.

The COVID-19 pandemic caused death of 6 million lives globally, primarily from respiratory failure, but also a significant number from invasive fungal co-infections in these patients, owing to the immune dysfunction in hospitalized patients. Such complications occurred more often in critically ill, hospitalized patients particularly those admitted in intensive care units and were reported as the major reason associated with a high mortality rate worldwide. Fungal pathogens most commonly associated with COVID-19 patients comprise members of the Mucorales (such as Rhizopus, Mucor, and Lichtheimia), as well as genera Aspergillus and Candida. In India, the prevalence rate of mucormycosis is relatively high than aspergillosis and candidiasis, and the predisposing risk factors associated with such infections included uncontrolled diabetes, underlying lung disease, leukopenia, neutropenia, malignancies and prolonged steroid therapy. However, co-infection with other fungi, including Alternariaand Scedosporium was also sporadically reported. These devastating invasive fungal infections are associated with differential mortality (high-low) and morbidity rates even after active management. The diagnosis of such infections is often challenging due to lack of sensitivity in contemporary diagnostic methods and poses an enormous challenge to healthcare experts. Thus, the role of early and accurate diagnosis, and management of such fungal infections, is vital in preventing life-threatening situations. Hence, this review focusses primarily on the epidemiology, predisposing risk factors, host environment, diagnosis and treatment of the most common medically important invasive fungal infections in immunocompromised conditions associated with COVID-19.

A basement membrane-related signature for prognosis and immunotherapy benefit in bladder cancer based on machine learning

BackgroundBladder cancer has a poor clinical outcome because of its high aggressiveness. Basement membrane plays vital functions in tumor invasion and migration. Invasion and distant metastasis of cancer are facilitated by degradation of the basement membrane and extracellular matrix.MethodsTen machine learning methods were utilized to develop the basement membrane-related signature (MRS) using datasets from TCGA, GSE13507, GSE31684, GSE32984 and GSE48276. Three anti-PD1 or anti-CTLA4 datasets and several predicting scores were used to investigate the performance of MRS in predicting the immunotherapy benefits.ResultsA predicting model based on the Enet algorithm (alpha = 0.1) was chosen as the optimal MRS since it had the highest average C-index being 0.72. According to TCGA data, the MRS showed good performance in predicting bladder cancer patients' clinical outcomes, with area under curves of 0.744, 0.766 and 0.817 for 1, 3, and 5-year receiver operating characteristic curve, respectively. PD1 and CTLA4 immunophenoscopes were associated with a low MRS score, as well as a lower tumor immune dysfunction and exclusion score. As MRS score increased, immune-activated cells levels decreased, tumor immune dysfunction and exclusion score decreased, immune escape score decreased, intratumor heterogeneity score decreased, PD1&CTLA4 immunophenoscore increased, and tumor mutational burden score increased in bladder cancer, suggesting better immunotherapy benefits. Bladder cancer cases with high MRS score was correlated with higher cancer related hallmark scores, including NOTCH and glycolysis signaling.ConclusionA new MRS has been developed for bladder cancer, which could be used to predict prognosis and the success of immunotherapy.

A Rare Case of TP63-Associated Lymphopenia Revealed by Newborn Screening Using TREC

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C&gt;T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly–Ectodermal Dysplasia–Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions.

Metabolomic analysis reveals potential role of immunometabolism dysregulation in recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects women's reproductive health seriously, with immune dysfunction playing a key role in its cause, yet the exact mechanisms remain elusive. We aim to investigate potential mechanisms and identify biomarkers linked to RPL. Immune cytokine testing and metabolomic profiling were conducted on the serum of 34 RPL patients and 30 healthy individuals. The metabolic pathways of the differential metabolites were analyzed, and specific metabolites were validated through targeted profiling. Potential biomarkers were identified, and the relationships between immune cytokines and differential metabolites were explored. In the RPL group, serum interleukin-6 and interleukin-10 levels were significantly higher, while interleukin-2 and interferon-γ were significantly lower. A total of 296 differential metabolites were detected by untargeted metabolomic profiling between the RPL and control groups, with most linked to amino acid metabolism. Targeted metabolomic profiling of amino acid metabolism revealed upregulation of indole-3-acetic acid, tyrosine, glycine, isoleucine, tryptophan, lysine, aspartic acid, arginine, leucine, threonine, glutamic acid, cystine, and phenylpyruvic acid (PPA) in the RPL group. Moreover, PPA and 5-hydroxy-L-tryptophan showed great potential in predicting RPL in a diagnostic model. Cystine and tyrosine were associated with immune cytokines in correlation analysis. The study highlights the role of amino acid metabolism in RPL pathogenesis, suggesting that PPA and 5-HTP may be potential predictive indicators, while cystine and tyrosine may potentially regulate immune responses related to RPL. Further investigation into the molecular mechanisms underlying these findings could potentially result in the creation of novel diagnostic and therapeutic approaches for RPL.

Modeling Parkinson's disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines.

Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.

Integrative bioinformatics analysis for identifying the mitochondrial-related gene signature associated with immune infiltration in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a reproductive disorder characterized by the cessation of ovarian function before the age of 40. Although mitochondrial dysfunction and immune disorders are believed to contribute to ovarian damage in POI, the interplay between these factors remains understudied. In this research, transcriptomic data related to POI were obtained from the NCBI GEO database. Hub biomarkers were identified through the construction of a protein‒protein interaction (PPI) network and further validated using RT‒qPCR and Western blot. Moreover, their expression across various cell types was elucidated via single-cell RNA sequencing analysis. A comprehensive investigation of the mitochondrial and immune profiles of POI was carried out through correlation analysis. Furthermore, potential therapeutic agents were predicted utilizing the cMap database. A total of 119 mitochondria-related differentially expressed genes (MitoDEGs) were identified and shown to be significantly enriched in metabolic pathways. Among these genes, Hadhb, Cpt1a, Mrpl12, and Mrps7 were confirmed both in a POI model and in human granulosa cells (GCs), where they were found to accumulate in GCs and theca cells. Immune analysis revealed variations in macrophages, monocytes, and 15 other immune cell types between the POI and control groups. Notably, strong correlations were observed between seven hub-MitoDEGs (Hadhb, Cpt1a, Cpt2, Mrpl12, Mrps7, Mrpl51, and Eci1) and various functions, such as mitochondrial respiratory complexes, dynamics, mitophagy, mitochondrial metabolism, immune-related genes, and immunocytes. Additionally, nine potential drugs (calyculin, amodiaquine, eudesmic acid, cefotaxime, BX-912, prostratin, SCH-79797, HU-211, and pizotifen) targeting key genes were identified. Our results highlight the crosstalk between mitochondrial function and the immune response in the development of POI. The identification of MitoDEGs could lead to reliable biomarkers for the early diagnosis, monitoring, and personalized treatment of POI.

Caspase-8 in inflammatory diseases: a potential therapeutic target.

Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.

Cytokines – regulators of immunity

This short review focuses on cytokines, molecular mediators of immunity and many other physiological functions of the body. Research on cytokines revealed new principles of cell-tocell communications and new paradigms in intracellular signal transduction. A few recombinant cytokines and, paradoxically, some cytokine inhibitors found practical use in medicine.

Targeting CD3-CD16+CD56+ NK Cells and NK Cell Activity by Intralipid in the Management of Reproductive Failure

Immunological risk factors in recurrent pregnancy loss include autoantibodies, alterations in NK cell number and function, regulatory T cells, the human leukocyte antigen system (HLA), etc., where the treatment options aim to regulate immune dysfunction. Intralipid is a synthetic product traditionally used as a dietary supplement consisting of soybean oil combined with refined egg phospholipids. It has been shown that intralipid exerts physiologic activities, including altering immunological functions, that may benefit patients with certain types of infertility. In this review, we summarize the current state of the art of targeting NK cells and NK cell activity in women with implantation failure or/and recurrent pregnancy loss. We focus on intralipid mechanisms of action and outcomes of clinical trials regarding the efficacy and safety of intralipid infusions in women with reproductive failure. More studies are needed to reveal all the aspects of the safety and effectiveness of intralipid administration in reproductive failure treatment.

Alterations and clinical value of peripheral lymphocyte subsets and inflammatory factors in paragangliomas.

Given the pivotal role of immune and inflammatory responses in tumor patients, the present study aimed to explore alterations and the clinical value of peripheral lymphocyte subsets and inflammatory factors in pheochromocytomas/paragangliomas (PPGLs). The clinical data of 327 patients, including 102 patients with metastatic PPGLs, were retrospectively analysed. Peripheral lymphocyte subsets were determined by flow cytometry. Relationships between immune and inflammatory parameters and clinicopathological characteristics were evaluated by intergroup comparisons and correlation analyses. Univariate and multivariate logistic regression analyses were employed to identify metastatic indicators. The corresponding nomogram was constructed and evaluated for discrimination and calibration. The median age at diagnosis was 45.0 years, and duration of follow-up was 3.0 years. Compared with those in younger patients (<45.0 years), most lymphocyte subsets were significantly reduced in older patients (≥45 years) (P<0.05). The count of lymphocytes, CD3+T cells and CD4+T cells were negatively correlated with 24h-urinary epinephrine and plasma metanephrine levels (R=-0.2∼-0.1, P<0.05). In addition, patients with lymph node (n=37) or bone metastases (n=41) had a lower percentage of CD4+T cells (P<0.05). Multivariate analysis revealed that CD3+T cell≥1446.50/μl, CD4+T cell%<39.95%, CD8+T cell%<24.95%, CD4+/CD8+T cell ratio<2.88, B cell%≥8.65%, TNF-alpha<12.45pg/ml, IL8<30.50pg/ml and PLT≥269.50*109/L were significant indicators of metastatic PPGLs. The area under the curve (AUC) of the nomogram was 0.800 (95% CI: 0.736-0.865). Immunesenescence, characterized by immune dysfunction with aging, was observed in PPGLs. Higher epinephrine and metanephrine levels might impair host's immune response. Monitoring changes in peripheral lymphocyte subsets and serum cytokines could indicate patients' conditions, especially the occurrence of metastasis.

Network Analysis of Dysregulated Immune Response to COVID-19 mRNA Vaccination in Hemodialysis Patients

Introduction: End-stage renal disease (ESRD) results in immune dysfunction that is characterized by both systemic inflammation and immune incompetence, leading to impaired responses to vaccination. Methods: To unravel the complex regulatory immune interplay in ESRD, we performed the network-based transcriptomic profiling of ESRD patients on maintenance hemodialysis (HD) and matched healthy controls (HCs) who received the two-dose regimen of the COVID-19 mRNA vaccine BNT162b2. Results: Co-expression networks based on blood transcription modules (BTMs) of genes differentially expressed between the HD and HC groups revealed co-expression patterns that were highly similar between the two groups but weaker in magnitude in the HD compared to HC subjects. These networks also showed weakened coregulation between BTMs within the dendritic cell (DC) family as well as with other BTM families involved with innate immunity. The gene regulatory networks of the most enriched BTMs, likewise, highlighted weakened targeting by transcription factors of key genes implicated in DC, natural killer (NK) cell, and T cell activation and function. The computational deconvolution of immune cell populations further bolstered these findings with discrepant proportions of conventional DC subtypes, NK T cells, and CD8+ T cells in HD subjects relative to HCs. Conclusion: Altogether, our results indicate that constitutive inflammation in ESRD compromises the activation of DCs and NK cells, and, ultimately, their mediation of downstream lymphocytes, leading to a delayed but intact immune response to mRNA vaccination.

Combination treatment with monoclonal antibodies for the management of severe asthma and immune-mediated inflammatory diseases: a comprehensive review.

Biological drugs have revolutionized the management of severe asthma, and a tailored treatment approach made it possible to consider remission as an achievable treatment target. The incidence of autoimmune diseases is increasing in many parts of the world. Patients suffering from severe asthma, eligible or already treated with an asthma-approved biologic agent, may suffer from another immune-mediated inflammatory disease (IMID) that could require the simultaneous use of a second monoclonal antibody. The real-life studies available in the literature describing the concurrent administration of an asthma-approved biologic agent with another biologic for a different immune disease, obtained through a systematic search on online databases based on monoclonal antibodies, were collected and analyzed. 26 articles were included in this review according to the prespecified inclusion and exclusion criteria. All included papers were retrospective in nature. Study designs were case reports (n=18), case series (n=3), retrospective chart reviews (n=3), retrospective observational studies (n=1), and cohort studies (n=1). The study is intended to present, within the current literature, all the administered combinations of severe asthma-approved biologics with monoclonal antibodies for a different indication. Those were grouped according to the IMID for whom the second biologic agent, with a different mechanism of action, was prescribed. The combinations prescribed to the cohort of patients specifically treating uncontrolled severe asthma were deeper evaluated in the discussion section, since an analysis of these therapeutic combinations deriving from real-life experiences may be useful to optimize the management of patients with severe asthma, ultimately leading to improved patient care and outcomes. Prospective registries and future studies are required to assess the safety and efficacy of combination therapies for severe asthmatic patients who suffer from an IMID.

Growth hormone - releasing hormone in the immune system.

GHRH is a neuropeptide associated with a diverse variety of activities in human physiology and immune responses. The present study reviews the latest information on the involvement of GHRH in the immune system and inflammation, suggesting that GHRH antagonists may deliver a new therapeutic possibility in disorders related to immune system dysfunction and inflammation.

Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame?

Systemic lupus erythematosus (SLE or lupus) is an immune-mediated disease associated with substantial medical burden. Notably, lupus exhibits a striking female bias, with women having significantly higher susceptibility compared to men, up to 14-fold higher in some ethnicities. Supernumerary X chromosome syndromes, like Klinefelter (XXY) and Triple X syndrome (XXX), also present higher SLE prevalence, whereas Turner syndrome (XO) displays lower prevalence. Taken together, SLE prevalence in different X chromosome dosage sceneries denotes a relationship between the number of X chromosomes and the risk of developing lupus. The dosage of X-linked genes, many of which play roles in the immune system, is compensated between males and females through the inactivation of one of the two X chromosomes in female cells. X-chromosome inactivation (XCI) initiates early in development with a random selection of which X chromosome to inactivate, a choice that is then epigenetically maintained in the daughter cells. This process is regulated by the X-Inactive-Specific Transcript (XIST), encoding for a long non-coding RNA, exclusively expressed from the inactive X chromosome (Xi). XIST interacts with various RNA binding proteins and chromatin modifiers to form a ribonucleoprotein (RNP) complex responsible for the transcriptional silencing and heterochromatinization of the Xi. This ensures stable silencing of most genes on the X chromosome, with only a few genes able to escape this process. Recent findings suggest that the molecular components involved in XCI, or their dysregulation, contribute to the pathogenesis of lupus. Indeed, nonrandom XCI, elevated gene escape from XCI, and the autoimmune potential of the XIST RNP complex have been suggested to contribute to auto-immune diseases, such as lupus. This review examines these current hypotheses concerning how this dosage compensation mechanism might impact the development of lupus, shedding light on potential mechanisms underlying the pathogenesis of the disease.

The Role of Interleukin-24 and Downstream Pathways in Inflammatory and Autoimmune Diseases.

Inflammatory and autoimmune diseases are pathological immune disorders and pose significant public health challenges due to their impact on individuals and society. Cytokine dysregulation plays a critical role in the development of these disorders. Interleukin (IL)-24, a member of the IL-10 cytokine family, can be secreted by various cell types, including immune and non-immune cells. The downstream effects of IL-24 upon binding to its receptors can occur in dependence on, or independently of, the Janus kinase (JAK)/signal transducer and the activator of transcription (STAT) signaling pathway. IL-24 and its downstream pathways influence crucial processes such as cell differentiation, proliferation, apoptosis, and inflammation, with its role varying across different diseases. On the one hand, IL-24 can inhibit the activation of pathogenic cells and autoimmune responses in autoimmune ocular diseases; on the other hand, IL-24 has been also implicated in promoting tissue damage by fostering immune cell activation and infiltration in psoriasis and allergic diseases. It suggests that IL-24, as a multifunctional cytokine, has complex regulatory functions in immune cells and related diseases. In this paper, we summarize the current knowledge on IL-24's immunomodulatory actions and its involvement in inflammatory and autoimmune disorders. Such insights may pave the way for novel therapeutic strategies for these diseases.

Adalimumab: A key element in the treatment strategy for immune-mediated inflammatory diseases: A review

Adalimumab is a biological drug effectively used in the treatment of several immune-mediated inflammatory diseases, including ankylosing spondylitis, juvenile idiopathic arthritis, and psoriasis. This study analyzed the therapeutic and economic benefits of adalimumab. Patients with ankylosing spondylitis showed significant improvements in quality of life and work productivity after treatment with adalimumab, confirming its clinical and economic efficacy. In the case of juvenile idiopathic arthritis and psoriasis, adalimumab demonstrated high efficacy and safety, significantly improving patients' conditions, establishing it as the gold standard of therapy. The use of adalimumab biosimilars offers accessible alternatives to the original drugs, expanding treatment options and reducing the economic burden on patients.

Acne and rosacea: similarities and differences. A review

Acne and rosacea are frequently encountered in the clinical practice of a dermatologist. These diseases can develop simultaneously in the same patient. Most often, the erythematous form of rosacea is combined with acne. Because of the similarity of clinical manifestations with acne, the diagnosis of rosacea can be easily missed. Common pathogenetic factors in the 2 diseases are thought to be genetics, alterations in the microbiome, immune disorders, and skin barrier dysfunction. There are few works addressing the relationship between acne and rosacea. A recent study identified a number of common differentially expressed genes, including interleukin-1B and matrix metalloproteinase 9, and showed that gamma delta T cells may play an important role in the development of both diseases. Despite the common pathogenesis and the similarity of some clinical manifestations (papules and pustules), acne and rosacea must be distinguished. In rosacea, there is persistent facial erythema induced by vasoregulatory neutropeptides, whereas in acne, the inflammatory process is due to excess sebum and changes in the skin microbiome. Isotretinoin is used for systemic therapy of both diseases. The drug affects the level of some cytokines, including inhibiting the expression of matrix metalloproteinase 9. In addition, it reduces sebum production in acne, and due to its ability to alter the skin microenvironment, it can reduce Propionibacterium acnes in acne and Demodex folliculorum in rosacea. Daily and cumulative doses for rosacea and acne will differ, as will topical therapy for these conditions. For acne, the combination of clindamycin and benzoyl peroxide is well established for the treatment of acne, allowing rapid meaningful clinical effect. In rosacea, metronidazole in cream form, which has better tolerability, is recommended as a topical agent. In patients suffering from both diseases simultaneously, a combination of clindamycin and benzoyl peroxide should be used to relieve acute inflammation, after which it is possible to switch to metronidazole.

Helicobacter pylori and Its Treatment Impact on Immune-Mediated Ocular Diseases

ABSTRACT Purpose Helicobacter pylori (HP), which colonizes exclusively in the gastrointestinal tract, has been reported to dysregulate the immune response and gives rise to several extra-gastrointestinal autoimmune disorders. However, the relationship between HP and immune-mediated ocular diseases remains ambiguous. This study aims to clarify the association between immune-mediated ocular diseases and HP infection, as well as the impact of HP treatment on the incidence of immune-mediated ocular diseases. Methods This is a retrospective population-based study using National Health Insurance Research Database in Taiwan. Patients with newly diagnosed peptic ulcer disease or HP infection between 2009 and 2015 were identified as HP group and compared to the non-HP group with one-to-one exact matching. Moreover, the incident risk of immune-mediated ocular diseases and its two subgroups (ocular surface and orbital inflammation group, intraocular inflammation group) were compared in HP patients with or without treatment. Results A total of 1,030,119 subjects in the non-HP group and 1,030,119 patients in the HP group were enrolled. The incidence rate of immune-mediated ocular diseases was significantly higher in the HP group (95% confidence interval (CI): 2.534–2.547). The incident rate ratio was significantly higher in HP with treatment than without treatment (HR: 1.654, 95% CI: 1.641–1.668). The Cox proportional hazards regression model demonstrated a significantly increased HR of immune-mediated ocular diseases in HP treated group (HR: 2.265, 95% CI: 2.024–2.534) and less increased HR in HP non-treated group (HR: 1.427, 95% CI: 1.273–1.598) when comparing to non-HP group. Subgroup analysis demonstrated a significantly higher incidence rate of ocular surface and orbital inflammation as well as intraocular inflammation in the HP group. Conclusion This study illustrated a higher incidence of immune-mediated ocular diseases in HP infection, and a heightened risk following HP eradication.

7925 Cowden Disease Occurring in Association with Common Variable Hypogammaglobulinemia: A Case Report

Abstract Disclosure: M.K. Shakir: None. I.C. Ebrahim: None. D.B. Maxwell: None. N.O. Vietor: None. T.D. Hoang: None. Carriers of a pathogenic germline mutations in the PTEN gene, a tumor suppressor gene, are at increased risk of multiple benign and malignant tumors, including thyroid, breast, endometrial and colon cancer, termed as PTEN Hamartoma Tumor Syndrome (PHTS). Recent studies have shown that PHTS patients may also have an increased risk of immunological dysregulation, such as autoimmunity and immune deficiencies. We are reporting a 47-year-old female with Cowden disease (CD) and common variable hypogammaglobulinemia (CVH). Our patient was diagnosed with CVH at the age of 25 after several episodes of pneumonia as well as poor wound healing. Since then, she is being treated with monthly intravenous immunoglobulin therapy. At the age of 24 years, she had a fainting episode and a diagnosis of gangliocytoma of cerebellum was made and she underwent resection of the tumor. At this time, she was also diagnosed with CD. She has a personal history of multiple other tumors including phyllodes tumor of breast, s/p bilateral mastectomy at the age of 32, status post hysterectomy for endometrial hyperplasia at the age 35. Hurthle cell adenomas of thyroid s/p total thyroidectomy at the age of 38. Her family history was significant for sister and father with CD. Physical examination was remarkable for only acral keratosis without mucocutaneous neuromas, oral papillomas and trichilemmomas. Cowden syndrome is the best-described phenotype of PHTS; it is characterized by mucocutaneous lesions and an elevated risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as various benign manifestations such as macrocephaly and dysplastic gangliocytoma of the cerebellum. Our patient was diagnosed with CD when she presented with gangliocytoma of the cerebellum. Immunodeficiency has been reported previously in patients with CD, and these patients often present with recurrent cellulitis and abscesses, and reduced T cell numbers and in vitro T cell proliferative function. Thus, PHTS patients may also have an increased risk of immunological dysregulation, such as autoimmunity and immune deficiencies. Additionally, a decreased ability of dendritic cells to prime CD8+ T cells may occur, leading to impaired tumor eradication. Immune dysfunction in PHTS patients might be a potentially manageable contributing factor to the increased cancer risk in PHTS. In conclusion, patients presenting with CD should also be screened for disorders of immunological dysregulation. Presentation: 6/2/2024