Low CD4 + T cell count is related to specific anti-nuclear antibodies, IFNα protein positivity and disease activity in systemic lupus erythematosus pregnancy.

BACKGROUND: Lymphopenia, autoantibodies and activation of the type I interferon (IFN) system are common features in systemic lupus erythematosus (SLE). We speculate whether lymphocyte subset counts are affected by pregnancy and if they relate to autoantibody profiles and/or IFNα protein in SLE pregnancy. METHODS: Repeated blood samples were collected during pregnancy from 80 women with SLE and 51 healthy controls (HC). Late postpartum samples were obtained from 19 of the women with SLE. Counts of CD4 + and CD8 + T cells, B cells and NK cells were measured by flow cytometry. Positivity for anti-nuclear antibodies (ANA) fine specificities (double-stranded DNA [dsDNA], Smith [Sm], ribonucleoprotein [RNP], chromatin, Sjögren's syndrome antigen A [SSA] and B [SSB]) and anti-phospholipid antibodies (cardiolipin [CL] and ß2 glycoprotein I [ß2GPI]) was assessed with multiplexed bead assay. IFNα protein concentration was quantified with Single molecule array (Simoa) immune assay. Clinical data were retrieved from medical records. RESULTS: Women with SLE had lower counts of all lymphocyte subsets compared to HC throughout pregnancy, but counts did not differ during pregnancy compared to postpartum. Principal component analysis revealed that low lymphocyte subset counts differentially related to autoantibody profiles, cluster one (anti-dsDNA/anti-Sm/anti-RNP/anti-Sm/RNP/anti-chromatin), cluster two (anti-SSA/anti-SSB) and cluster three (anti-CL/anti-ß2GPI), IFNα protein levels and disease activity. CD4 + T cell counts were lower in women positive to all ANA fine specificities in cluster one compared to those who were negative, and B cell numbers were lower in women positive for anti-dsDNA and anti-Sm compared to negative women. Moreover, CD4 + T cell and B cell counts were lower in women with moderate/high compared to no/low disease activity, and CD4 + T cell count was lower in IFNα protein positive relative to negative women. Finally, CD4 + T cell count was unrelated to treatment. CONCLUSION: Lymphocyte subset counts are lower in SLE compared to healthy pregnancies, which seems to be a feature of the disease per se and not affected by pregnancy. Our results also indicate that low lymphocyte subset counts relate differentially to autoantibody profiles, IFNα protein levels and disease activity, which could be due to divergent disease pathways.

Disseminated cryptococcosis in a patient with idiopathic CD4 + T lymphocytopenia presenting as prostate and adrenal nodules: diagnosis from pathology and mNGS, a case report.

Disseminated Cryptococcosis infection typically occurs in immunocompromised patients, often manifested as pneumonia or meningoencephalitis. Cases with involvement of either prostate or adrenal glands are less frequent. We describe a case of an immunocompromised 62-year-old man with new-found Idiopathic CD4 + T lymphocytopenia who presented with urinary irritation symptoms followed by headache. The patient was finally diagnosed as disseminated cryptococcosis of prostate, adrenal gland involvement with the help of combining histopathology of formalin-fixed, paraffin-embedded tissue with metagenomic next-generation sequencing technique to identify C neoformans sensu stricto in prostate, adrenal gland tissues. Clinicians should be aware of atypical presentations of cryptococcal disease. In this case of cryptococcosis in immunocompromised patients, we find that cryptococcosis can affect varied organs simultaneously and should be considered in the differential of infectious diseases. And mNGS technology helps to confirm the diagnosis.

Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

Disseminated Cryptococcosis in Idiopathic CD4+ Lymphocytopenia.

INTRODUCTION: Idiopathic CD4+ Lymphocytopenia (ICL) is a rare entity grouped in non- HIV-related syndromes. ICL is characterized by a marked low CD4 T cell count of <300 cells/mm3 with ambiguous natural history and prognosis. In addition, cryptococcal and nontuberculous mycobacterial infections are reported as known opportunistic infections. Therefore, management turns around vigilant follow-up and treatment of the current clinical scenario of these patients. CASE PRESENTATION: Here, a 55-year-old lady was referred with a history of diffuse headache and intermittent fever for two months, projectile vomiting, and altered mental status for five days. Nonpruritic maculopapular rashes and diffuse desquamation of the skin were noted. She had no significant previous medical history. Based on clinical findings and investigations, she was diagnosed with ICL having disseminated cryptococcosis. Unfortunately, the patient did not undergo specific treatment as she was recognized late, and unfortunately, she died. CONCLUSION: It is of paramount importance to recognize the clinical entity as early as possible to start appropriate treatment, which may positively impact the outcome. Therefore, the clinician must be aware of disseminated cryptococcosis associated with non-HIV states.

Disseminated cryptococcosis with varicella-zoster virus coinfection of idiopathic CD4 + T lymphocytopenia: a case report and literature review.

BACKGROUND: Idiopathic CD4 + T lymphocytopenia (ICL) is a rare immunodeficiency syndrome, unaccompanied by various opportunistic infections. Cryptococcus and varicella-zoster viruse are the most common opportunistic infections. METHOD: We described a case of disseminated cryptococcosis with varicella-zoster virus coinfection in a patient with ICL and reviewed all published reports. A total of 26 cases with cryptococcal meningitis in ICL were enrolled. DISCUSSION: ICL remains poorly understood to clinicians. Patients with cryptococcal meningitis in ICL mostly suffered with headache and fever in a subacute or chronic period, while some patients might have atypical manifestations which makes a difficulty for early diagnosis. Some characteristics of cerebrospinal fluid can help to predict the prognosis of the disease. Cryptococcosis with varicella-zoster virus coinfection is rare but serious. CONCLUSION: We recommed CD4 + T cells should be assessed in patients with unusual or recurrent infections. As the underlying pathophysiology is poorly understood, there is no standard therapy for ICL. Increased awareness of the disease and early prevention for CD4 reduction are needed.

The oncolytic virus VT09X optimizes immune checkpoint therapy in low immunogenic melanoma.

Tumors with a low level of pre-existing immune cell infiltration respond poorly to immune checkpoint therapies. Oncolytic viruses optimize immunotherapies by modulating the tumor microenvironment and affecting multiple steps in the cancer-immunity cycle, making them an attractive agent for combination strategies. We engineered an HSV-1-based oncolytic virus and investigated its antitumor effects in combination with the marketed PD-1 antibody Keytruda (pembrolizumab) in hPD-1 knock-in mice bearing non-immunogenic B16-F10 melanoma. Our results showed enhanced CD8+ and CD4+ T cell infiltration, IFN-γ secretion and PD-L1 expression in tumors, subsequently leading to the prolonged overall survival of mice. Systemic changes in lymphocyte cell proportions were also observed in the peripheral blood. In summary, these findings provide evidence that oncolytic viruses can be engineered as a potential platform for combination therapies, especially to treat tumors that are poorly responsive to immune checkpoint therapy.

"Burnt-out" progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia.

Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by John Cunningham virus (JCV) infection; however, a growing number of PML patients now survive longer and achieve remission, largely due to the advent of combination antiretroviral therapy. Several reports have suggested that the pathology in such patients presents only chronic demyelination without characteristic cellular changes, being referred to as "burnt-out" PML. On the other hand, our knowledge of "burnt-out" PML is still substantially limited, especially in patients with non-human immunodeficiency virus infection. Here, we report a case of PML associated with idiopathic CD4+ lymphocytopenia (ICL) who presented with spontaneous remission and survived for 11 years after onset. Notably, postmortem examination revealed surprisingly broad "burnt-out" lesions lacking the classic histopathological findings. However, pathogenic JCV-specific DNA sequences was still present in the autopsied brain tissue. This case suggests that complete remission can be achieved with a persistent presence of JCV-specific pathogenic sequences, even after a catastrophic infection. Considering that there have been a few reported cases of PML with ICL with long survival, the long-term survival of our case may share a favorable immunological response that is unique to a subgroup of ICL.

Alisol B 23-acetate, a new promoter for cholesterol efflux from dendritic cells, alleviates dyslipidemia and inflammation in advanced atherosclerotic mice.

Atherosclerosis (AS) is characterized by dyslipidemia and chronic inflammation. In the high-fat environment, the lipid metabolism of dendritic cells (DCs) is abnormal, which leads to abnormal immune function, promotes the occurrence of immune inflammatory reactions, and promotes the development of AS. Alisol B 23-acetate (23B) is a triterpenoid in the rhizomes of Alisma, which is a traditional Chinese medicine. Here, we identified cholesterol metabolism-related targets of 23B through a virtual screen, and further transcriptome analysis revealed that 23B can change antigen presentation and cholesterol metabolism pathways in cholesterol-loaded DCs. In vitro experiments confirmed that 23B promoted cholesterol efflux from ApoE-/- DCs, reduced the expression of MHC II, CD80, and CD86, and inhibited the activation of CD4+ T cells and the production of inflammatory cytokines IL-12 and IFN-γ. In advanced AS mice, 23B can decrease triacylglycerol (TG) levels and increase high-density lipoprotein-cholesterol (HDL-C) levels in plasma and the expression of cholesterol efflux genes in the aorta. Neither helper T cells 1 (Th1) nor regulatory T cells (Tregs) in peripheral blood changed significantly in the presence of 23B, but 23B reduced the levels of IL-12 and IFN-γ in serum. However, 23B did not change the total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in serum or lipid accumulation in the aorta. Moreover, 23B did not increase the production of IL-10 and TGF-ß1 in vivo or in vitro. These results indicate that 23B promotes cholesterol efflux from DCs, which can improve the immune inflammatory response and contribute to controlling the inflammatory status of AS.

Pre-clinical evaluation of a whole-parasite vaccine to control human babesiosis.

Babesia spp. are tick-transmitted intra-erythrocytic protozoan parasites that infect humans and animals, causing a flu-like illness and hemolytic anemia. There is currently no human vaccine available. People most at risk of severe disease are the elderly, immunosuppressed, and asplenic individuals. B. microti and B. divergens are the predominant species affecting humans. Here, we present a whole-parasite Babesia vaccine. To establish proof-of-principle, we employed chemically attenuated B. microti parasitized red blood cells from infected mice. To aid clinical translation, we produced liposomes containing killed parasite material. Vaccination significantly reduces peak parasitemia following challenge. B cells and anti-parasite antibodies do not significantly contribute to vaccine efficacy. Protection is abrogated by the removal of CD4+ T cells or macrophages prior to challenge. Importantly, splenectomized mice are protected by vaccination. To further facilitate translation, we prepared a culture-based liposomal vaccine and demonstrate that this performs as a universal vaccine inducing immunity against different human Babesia species.

Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer.

Induced pluripotent stem cells (iPSCs) and cancer cells share cellular similarities and transcriptomic profiles. Here, we show that an iPSC-based cancer vaccine, comprised of autologous iPSCs and CpG, stimulated cytotoxic antitumor CD8+ T cell effector and memory responses, induced cancer-specific humoral immune responses, reduced immunosuppressive CD4+ T regulatory cells, and prevented tumor formation in 75% of pancreatic ductal adenocarcinoma (PDAC) mice. We demonstrate that shared gene expression profiles of "iPSC-cancer signature genes" and others are overexpressed in mouse and human iPSC lines, PDAC cells, and multiple human solid tumor types compared with normal tissues. These results support further studies of iPSC vaccination in PDAC in preclinical and clinical models and in other cancer types that have low mutational burdens.

Analysis of specific antibody and cellular immune response to first-dose measles vaccine Edmonston-Zagreb in 9-month-old infants

Background: Measles vaccinations have been suggested to provide immune protection and decreased measles incidence. However, there was a limited study evaluating how the measles vaccine elicits specific immune responses. Objective: This study aimed to evaluate both humoral and cellular immunity to first-dose measles vaccine Edmonston-Zagreb (EZ) in 9-month-old Indonesian infants. Methods: A cohort study was conducted on 9-month-old infants who got the first-dose of measles vaccine EZ. Measles-specific immunoglobulin G (IgG) antibody serum levels were measured using plaque-reduction microneutralization assay. Peripheral blood mononuclear cells were stimulated with a measles-specific peptide to identify a cellular immune response. Quantification of CD4+ and CD8+ T-cells producing interferon-gamma (IFN-ɣ) and interleukin 17-A (IL-17A) were conducted by flow cytometry. Humoral and cellular immune response parameters were analyzed over time. Results: The prevalence of seropositivity rates was 85.8% at 1-month after vaccination and 16.67% at 6-months postvaccination. Measles-specific IgG antibodies increased significantly at 1-month after measles vaccination. However, they decreased significantly 6-months after vaccination. IFN-ɣ and IL-17A secreting T-cells increased significantly at 1-month after measles vaccination. Interestingly, a significant decrease of IFN-ɣ and IL-17A secreting CD4+ T cells was noticed 6-months postvaccination compared to IFN-ɣ and IL-17A secreting CD8+ T cells. Conclusion: Our study suggests that the first-dose measles vaccine on 9-months-old infants seems to induce both humoral and cellular immune responses that decline 6-months after vaccination (AU)

Characterization of autoantibodies, immunophenotype and autoimmune disease in a prospective cohort of patients with idiopathic CD4 lymphocytopenia.

OBJECTIVE: Characterize autoantibodies and autoimmune diseases in a prospective cohort of patients with Idiopathic CD4 Lymphocytopenia (ICL) a rare immunodeficiency characterized by an absolute CD4+ T count of <300 cells/µl in the absence of HIV or HTLV infection. METHODS: Single-Center prospective study of 67 patients conducted over an 11-year period. Rheumatologic evaluation and measurement of autoantibodies were systematically conducted, and flow cytometry of immune cell subsets was performed in a subset of patients. RESULTS: 54% of referred patients had clinical evidence of autoimmunity, with 34% having at least one autoimmune disease, most commonly autoimmune thyroid disease. 19%, had autoantibodies or incomplete features of autoimmune disease. Patients with autoimmune disease had more elevated serum immunoglobulins, and more effector memory T cells than those without autoimmunity. CONCLUSIONS: Evidence of autoimmunity, including autoimmune diseases, is more prevalent in ICL than the general population, and should be considered part of this syndrome.

Nuclear receptor LXRß controls fitness and functionality of activated T cells.

T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor ß (LXRß) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRß in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRß-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRß-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRß function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.

A splice acceptor variant in HLA-DRA affects the conformation and cellular localization of the class II DR alpha-chain.

Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen-derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/ß-heterodimers on the surface of professional antigen-presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA-DRA gene mediates the transcription of an alternative version of the α-chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA-DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding ß-chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide-binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA-DRA functions as a novel intact antigen for class II HLA molecules.

Pulmonary sarcoidosis: prognostic factors at diagnosis in patients from North of Portugal / Sarcoidosis pulmonar: factores pronósticos en el diagnóstico en enfermos del norte de Portugal

BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease that affects the lungs in more than 90% of the patients. It is associated with a variable clinical course and considering all the different forms of disease presentation, there are an absence of reliable clinical prognostic markers that can predict the outcome at diagnosis. OBJECTIVE: The aim of our study was to investigate prognostic factors at diagnosis in a population of sarcoidosis patients from Northern Portugal. METHODS: A group of 110 patients with chronic evolution was compared with 129 patients with disease resolution regarding their clinical, radiologic and laboratorial features. RESULTS: We found a positive association between the chronic forms and lung function impairment, radiologic stage II, lower lymphocyte CD4/CD8 and extrapulmonary disease. Löfgren syndrome and asthenia instead had a protective significant association to chronicity. Our final logistic regression model found a significant independent association between age (adjusted OR=1.06), extrapulmonary involvement (adjusted OR=2.68), Löfgren's syndrome (adjusted OR=0.15) with outcome toward chronicity. CONCLUSIONS: In this first study searching for prognostic factors at diagnosis in a Northern Portuguese population, we found clinical prognosis factors that have been described in other populations that should be considered whenever sarcoidosis is identified

INTRODUCCIÓN: La sarcoidosis es una enfermedad granulomatosa multisistémica que afecta a los pulmones en más del 90% de los enfermos. Está asociada a un curso clínico variable y, considerando todas las formas diferentes de presentación de la enfermedad, hay una ausencia de marcadores de pronóstico clínico confiables que puedan predecir el resultado en el momento del diagnóstico. OBJETIVO: El objetivo de nuestro estudio fue investigar los factores pronósticos en el momento del diagnóstico en una población de enfermos con sarcoidosis del norte de Portugal. MÉTODOS: Se comparó un grupo de 110 enfermos con evolución crónica con 129 enfermos con resolución de la enfermedad teniendo en cuenta sus características clínicas, radiológicas y de laboratorio. RESULTADOS: Se encontró una asociación positiva entre las formas crónicas y el deterioro de la función pulmonar, el estadio radiológico II, la relación CD4/CD8 más baja y la enfermedad extrapulmonar. Ya el síndrome de Löfgren y la astenia tuvieron una asociación protectora significativa con la cronicidad. Nuestro modelo de regresión logística final encontró una asociación independiente significativa entre la edad (OR ajustada=1,06), la afectación extrapulmonar (OR ajustada=2,68), el síndrome de Löfgren (OR ajustada=0,15) y el resultado hacia la cronicidad. CONCLUSIONES: En este primer estudio de búsqueda de factores pronósticos en el momento del diagnóstico en una población del norte de Portugal, fueron encontrados predictores clínicos, que se han descrito en otras poblaciones que se deben considerar cada vez que se hace el diagnóstico de una sarcoidosis

Leucoencefalopatía multifocal progresiva en paciente con lupus eritematoso sistémico: ¿podría ser la linfocitopenia-CD4+ el principal factor de riesgo? / Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus: Could CD4+ lymphopenia be the main risk factor?

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A Rare Case of Cerebellar Progressive Multifocal Leukoencephalopathy due to Idiopathic CD4 Lymphocytopenia.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by reactivation of JC virus during a time of cell mediated immune suppression. One potential rare cause of PML is Idiopathic CD4 lymphocytopenia (ICL) in which there is an unexplained deficit of CD4 T cells. We present a case of cerebellar PML in the absence of known immunosuppression leading to the diagnosis of ICL.

"Borderline" idiopathic CD4+ T-cell lymphocytopenia presenting with atypical progressive multifocal leukoencephalopathy.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare disorder characterized by low counts of CD4+ cells (<300/mm3) in absence of other known causes of immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in association with ICL with variable outcome. We describe the case of a 40 year-old man diagnosed with PML, which showed a monophasic course. Causes of primary and secondary immunodeficiency were ruled out, only a "borderline" ICL was found. This case highlights that a severe immunodepression could not be an absolute prerequisite in developing PML and also points the attention on current definition of ICL.