Exploring the Immunological Profile in Breast Cancer: Recent Advances in Diagnosis and Prognosis through Circulating Tumor Cells.

This review offers a comprehensive exploration of the intricate immunological landscape of breast cancer (BC), focusing on recent advances in diagnosis and prognosis through the analysis of circulating tumor cells (CTCs). Positioned within the broader context of BC research, it underscores the pivotal role of the immune system in shaping the disease's progression. The primary objective of this investigation is to synthesize current knowledge on the immunological aspects of BC, with a particular emphasis on the diagnostic and prognostic potential offered by CTCs. This review adopts a thorough examination of the relevant literature, incorporating recent breakthroughs in the field. The methodology section succinctly outlines the approach, with a specific focus on CTC analysis and its implications for BC diagnosis and prognosis. Through this review, insights into the dynamic interplay between the immune system and BC are highlighted, with a specific emphasis on the role of CTCs in advancing diagnostic methodologies and refining prognostic assessments. Furthermore, this review presents objective and substantiated results, contributing to a deeper understanding of the immunological complexity in BC. In conclusion, this investigation underscores the significance of exploring the immunological profile of BC patients, providing valuable insights into novel advances in diagnosis and prognosis through the utilization of CTCs. The objective presentation of findings emphasizes the crucial role of the immune system in BC dynamics, thereby opening avenues for enhanced clinical management strategies.

Diagnostic Value of Immunological Biomarkers in Children with Asthmatic Bronchitis and Asthma.

Background and Objectives: This study aimed to investigate the diagnostic value of immunological biomarkers in children with asthmatic bronchitis and asthma and to develop a machine learning (ML) model for rapid differential diagnosis of these two diseases. Materials and Methods: Immunological biomarkers in peripheral blood were detected using flow cytometry and immunoturbidimetry. The importance of characteristic variables was ranked and screened using random forest and extra trees algorithms. Models were constructed and tested using the Scikit-learn ML library. K-fold cross-validation and Brier scores were used to evaluate and screen models. Results: Children with asthmatic bronchitis and asthma exhibit distinct degrees of immune dysregulation characterized by divergent patterns of humoral and cellular immune responses. CD8+ T cells and B cells were more dominant in differentiating the two diseases among many immunological biomarkers. Random forest showed a comprehensive high performance compared with other models in learning and training the dataset of immunological biomarkers. Conclusions: This study developed a prediction model for early differential diagnosis of asthmatic bronchitis and asthma using immunological biomarkers. Evaluation of the immune status of patients may provide additional clinical information for those children transforming from asthmatic bronchitis to asthma under recurrent attacks.

Cytokine response as a biomarker for early diagnosis and outcome prediction of stem cell transplant recipients and acute leukemia patients with invasive aspergillosis.

We aimed to determine the role of serum cytokine expression in invasive aspergillosis (IA) diagnosis and outcome prediction in hematologic patients. In this multicenter study, serum cytokines (IL6, IL10, INF-gamma, IL12, IL4, TNF-alpha, IL17, and IL23) were prospectively recruited from all consecutive patients with hematologic malignances at IA diagnosis and compared to control patients matched by center, age, baseline disease, and therapeutic regimen. We included 36 patients with IA and 36 controls. Serum levels of IL6 and IL10 cytokines on day 0 were significantly increased in patients with IA when compared to controls (P = 0.001 and P = 0.025, respectively), even in those who were neutropenic. No differences were observed for the other cytokines. IL6 and IL10 predicted IA with an area under the ROC curve of 0.74 (95% CI 0.62-0.86) and 0.64 (95% CI 0.51-0.77), respectively. The best cutoff point in predicting IA was 20.85 pg/ml for IL6 (sensitivity 72.2%; specificity 77.8%; PPV 76.5% and NPV 73.7%), and 0.045 pg/ml for IL10 (sensitivity 62.9%; specificity 63.9%; PPV 62.9% and NPV 63.9%). IL6 levels were associated with increased mortality, with the best cutoff value being 65.59 pg/ml in mortality prediction. In conclusion, in addition to current tests in place, IL6 and IL10 levels-as measured in plasma-may help clinicians diagnose IA. High levels of IL6 at IA diagnosis are related with worse outcomes. LAY SUMMARY: We evaluated the role of serum cytokine expression in invasive aspergillosis (IA) diagnosis and outcome. Serum levels of IL6 and IL10 are increased in patients with IA compared to controls, and IL6 levels are associated with mortality.

CCL2 and IFN-γ serum levels as biomarkers for subclinical infection in household contacts of leprosy patients.

Leprosy, also known as Hansen's disease, is a long-term infection by the bacteria Mycobacterium leprae, and actually still persists as a serious public health problem. The clinical parameters are used for diagnosis, however, some studies have indicated the selection of a set of biomarkers of subclinical infection, both serological and cellular, that allow the early diagnosis. Some cytokines and chemokines have been differentially expressed in index cases (paucibacillary and multibacillary patients) and household contacts (HHC), and may present a potential biomarker of M. leprae subclinical infection. Thus, the aim of this study was to analyze the variations in the profile of cytokines and chemokines, longitudinally, between index cases and their household contacts with a view to identifying possible biomarkers with differential expression, which may guide the early subclinical infection in household contacts. A longitudinal study was carried out between 2014 and 2015. The serum levels of the cytokines and chemokines were measured in all patient samples by CBA (Cytometric Bead Array). We observed a reduction of IL-4 and IL-17 expression of HHC group in the second evaluation (T1), as also a reduction of IL-17 in MB. We observed increased expression of IL-2 in PB patients as well. HHC, PB and MB showed a similar reduction profile of the chemokines CXCL8, CXCL9 and CXCL10 from T0 to T1. Interestingly, only serological levels of CCL2 are increased after a follow-up of HHC group, and this group, but not PB and MB patients, showed a significant association and a negative correlation between CCL2 and IFN-γ. The present study showed for the first time a similarity in the immunological scenario between HHC, PB and MB patients. In addition, this work highlights CCL2 chemokine in association with IFN-γ as possible biomarkers of subclinical infection of HHC, as also a parameter of early infection monitoring.

Autoimmune biomarkers in porto-sinusoidal vascular disease: Potential role in its diagnosis and pathophysiology.

BACKGROUND AND AIMS: Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown. The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD. METHODS: Thirty-seven consecutive patients with PSVD and 39 with cirrhosis matched by gender, signs of portal hypertension and liver function were included (training set). By using Indirect Immunofluorescence, ELISA and slot-blot methods data 22 autoantibodies were identified in patients with PSVD and cirrhosis. Presence of anti-endothelial cells antibodies (AECA) was assayed by a cell-based ELISA. Thirty-one PSVD, 40 cirrhosis patients, 15 patients with splenomegaly associated with haematological disease and 14 healthy donors were included in a validation set. FINDINGS: The proportion of patients with at least one positive antibody was statistically significantly higher in patients with PSVD compared with cirrhosis (92% vs 56%; P < .01). Specifically, AECA were significantly more frequent in PSVD than in cirrhosis (38% vs 15%; P = .013). Results were confirmed in the validation set. In the overall population, presence of AECA had a 63% positive predictive value for diagnosing PSVD and a 71% negative predictive value, with a specificity of 94% when the 1/16 level is used as cut-off. AECA positive serum samples react with a 68-72 kDa protein of human liver endothelial sinusoidal cells.

Biomarkers associated with COVID-19 disease progression.

The coronavirus disease 2019 (COVID-19) pandemic is a scientific, medical, and social challenge. The complexity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is centered on the unpredictable clinical course of the disease that can rapidly develop, causing severe and deadly complications. The identification of effective laboratory biomarkers able to classify patients based on their risk is imperative in being able to guarantee prompt treatment. The analysis of recently published studies highlights the role of systemic vasculitis and cytokine mediated coagulation disorders as the principal actors of multi organ failure in patients with severe COVID-19 complications. The following biomarkers have been identified: hematological (lymphocyte count, neutrophil count, neutrophil-lymphocyte ratio (NLR)), inflammatory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT)), immunological (interleukin (IL)-6 and biochemical (D-dimer, troponin, creatine kinase (CK), aspartate aminotransferase (AST)), especially those related to coagulation cascades in disseminated intravascular coagulation (DIC) and acute respiratory distress syndrome (ARDS). New laboratory biomarkers could be identified through the accurate analysis of multicentric case series; in particular, homocysteine and angiotensin II could play a significant role.

Prospection of immunological biomarkers for characterization and monitoring of asymptomatic Leishmania (Leishmania) infantum infection.

In areas endemic for Leishmania infantum, an asymptomatic infection may be an indicator of the extent of transmission. The main goal of this study was to evaluate the applicability of measuring circulating immunological biomarkers as an alternative strategy to characterize and monitor L. infantum asymptomatic infections in combination with serological methods. To this end, 179 children from a region endemic for visceral leishmaniasis (VL), aged 1-10 years old, selected from a cross-sectional study, were identified as asymptomatic (n = 81) or uninfected (n = 98) by qPCR and/or serological tests (ELISA using L. infantum soluble antigen and rK39), and, together with serum samples of children diagnosed with VL (n = 43), were subjected to avidity tests and cytokine levels measurement. Avidity rates (AR) ranging from 41 to 70% were found in 29 children (66%) from the asymptomatic group. On the other hand, high AR (above 70%) were observed in 27 children (64%) from the VL group. Logistic Regression and Classification and Regression Tree (CART) analyses demonstrated that lower AR and IFN-γ production associated with higher IL-17A levels were hallmarks in asymptomatic L. infantum infections. Therefore, this study proposes an association of immunological biomarkers that can be used as a complementary strategy for the characterization and monitoring of asymptomatic VL infections in children living in endemic areas.

Cerebrospinal fluid immunological biomarkers associated with axonal damage in multiple sclerosis.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) neurofilament light protein (NFL) is a promising biomarker of axonal injury and neurodegeneration. Here CSF lymphocyte subpopulations and antibodies, potential players of neurodegeneration, are examined in relation to CSF NFL shedding in MS. METHODS: Cerebrospinal fluid NFL from 127 consecutive untreated MS patients was analysed. Samples from 37 age-matched patients with other central nervous system non-inflammatory neurological diseases (NIND) were also assessed. CD4+, CD8+, CD56+ and CD19+ cell subsets were studied by flow cytometry. Oligoclonal IgG and IgM bands (OCMB) against lipids were studied by isoelectric focusing and immunoblotting. These data were analysed in relation to clinical and magnetic resonance imaging features. RESULTS: A CSF NFL cut-off value of 900 ng/l (mean + 3 SD of NIND values) was calculated. MS patients with increased NFL values showed significantly higher Multiple Sclerosis Severity Score and magnetic resonance imaging lesion number. The presence of OCMB (P < 0.0001) and elevated T and B lymphocyte counts was associated with increased levels of CSF NFL. CONCLUSIONS: High CSF NFL levels are associated with elevated CSF lymphocyte cell counts and intrathecal synthesis of IgM against lipids. These findings support a role for OCMB in the axonal damage of MS offering a rationale for the association of these antibodies with disability and brain atrophy progression in MS.

Neutrophil-to-Lymphocyte Ratio and Cytokine Profiling as Predictors of Disease Severity and Survival in Unvaccinated COVID-19 Patients.

BACKGROUND: During the COVID-19 pandemic, identifying reliable biomarkers for predicting disease severity and patient outcomes in unvaccinated individuals is essential. This study evaluates the efficacy of key hematological markers, including leukocyte and neutrophil counts, Neutrophil-to-Lymphocyte Ratio (NLR), and cytokine profiles (IL-6, INF-γ, TNF-α, IL-17A, CCL2, and CXCL10) for predicting the necessity for mechanical ventilation and assessing survival probabilities. METHODS: We conducted an in-depth analysis on a cohort of COVID-19 patients, emphasizing the relationship between NLR, cytokine profiles, and clinical outcomes, utilizing routine leukocyte counting and cytokine quantification by flow cytometry. RESULTS: Elevated leukocyte and neutrophil counts, increased NLR, and significant cytokine elevations such as IL-6 and IL-10 were strongly associated with the need for mechanical ventilation, reflecting a pronounced systemic inflammatory response indicative of severe disease outcomes. CONCLUSION: Integrating hematological markers, particularly NLR and cytokine profiles, is crucial in predicting mechanical ventilation needs and survival in non-vaccinated COVID-19 patients. Our findings provide critical insights into the pathophysiology of COVID-19, supporting the development of more targeted clinical interventions and potentially informing future strategies for managing infectious disease outbreaks.

Clinical Characteristics and Patterns of Immune Responses in COVID-19 Patients From a Rural Community Hospital.

Background Although demographic and clinical factors such as age, certain comorbidities, and sex have been associated with COVID-19 outcomes, these studies were largely conducted in urban populations affiliated with large academic medical centers. There have been very few studies focusing on rural populations that also characterize broader changes in inflammatory cytokines and chemokines. Methodology A single-center study was conducted between June 2020 and March 2021 in Abilene, Texas, USA. Patients were included if they presented to the hospital for treatment of COVID-19, had extra biological materials from routine care available, and were between the ages of 0 to 110 years. There were no exclusion criteria. Patient characteristics, symptom presentation, and clinical laboratory results were extracted from electronic health records. Blood specimens were analyzed by protein microarray to quantitate 40 immunological biomarkers. Results A total of 122 patients were enrolled, of whom 81 (66%) were admitted to the general non-critical inpatient unit, 37 (30%) were admitted to the intensive or critical care units, and four (3.2%) were treated outpatient. Most hospitalized COVID-19 patients in this rural population were elderly, male, obese, and retired individuals. Predominant symptoms for non-critical patients were shortness of breath, fever, and fatigue. Ferritin levels for outpatient patients were lower on average than those in an inpatient setting and lactate dehydrogenase (LDH) levels were noted to be lower in non-critical and outpatient than those in the intensive care unit setting. Inflammatory biomarkers were positively correlated and consistent with inflammatory cascade. Interleukin (IL)-10 was positively correlated while platelet-derived growth factor was negatively correlated with inflammatory biomarkers. Patients ≥65 years had significantly higher levels of LDH and seven cytokines/chemokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin IL-1b, IL-6, IL-10, IL-11, macrophage inflammatory protein (MIP)-1d, and IL-8) while levels of five other immune molecules (intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein 1 (MCP-1), tissue inhibitor of metalloproteinase 2 (TIMP-2), IL-2, and IL-4) were significantly lower compared to those <65 years. Females had significantly higher levels of LDH and 10 cytokines/chemokines (GM-CSF, IL-1b, IL-6, IL-10, IL-11, IL-15, IL-16, MIP-1a, MIP-1d, and IL-8) while levels of TIMP-2 and IL-4 were significantly lower than male patients. Conclusions The clinical characteristics of this rural cohort of hospitalized patients differed somewhat from nationally reported data. The contributions of social, environmental, and healthcare access factors should be investigated. We identified age and sex-associated differences in immunological response markers that warrant further investigation to identify the underlying molecular mechanisms and impact on COVID-19 pathogenesis.

Autism spectrum disorder diagnosis using a new panel of immune- and inflammatory-related serum biomarkers: A case-control multicenter study.

Background and objectives: Children with autism spectrum disorder (ASD) present with distinctive clinical features. No objective laboratory assay has been developed to establish a diagnosis of ASD. Considering the known immunological associations with ASD, immunological biomarkers might enable ASD diagnosis and intervention at an early age when the immature brain has the highest degree of plasticity. This work aimed to identify diagnostic biomarkers discriminating between children with ASD and typically developing (TD) children. Methods: A multicenter, diagnostic case-control study trial was conducted in Israel and Canada between 2014 and 2021. In this trial, a single blood sample was collected from 102 children with ASD as defined in Diagnostic Statistical Manual of Mental Disorders [DSM)-IV (299.00) or DSM-V (299.00)], and from 97 typically developing control children aged 3-12 years. Samples were analyzed using a high-throughput, multiplexed ELISA array which quantifies 1,000 human immune/inflammatory-related proteins. Multiple logistic regression analysis was used to obtain a predictor from these results using 10-fold cross validation. Results: Twelve biomarkers were identified that provided an overall accuracy of 0.82 ± 0.09 (sensitivity: 0.87 ± 0.08; specificity: 0.77 ± 0.14) in diagnosing ASD with a threshold of 0.5. The resulting model had an area under the curve of 0.86 ± 0.06 (95% CI: 0.811-0.889). Of the 102 ASD children included in the study, 13% were negative for this signature. Most of the markers included in all models have been reported to be associated with ASD and/or autoimmune diseases. Conclusion: The identified biomarkers may serve as the basis of an objective assay for early and accurate diagnosis of ASD. In addition, the markers may shed light on ASD etiology and pathogenesis. It should be noted that this was only a pilot, case-control diagnostic study, with a high risk of bias. The findings should be validated in larger prospective cohorts of consecutive children suspected of ASD.

Severe Combined Immunodeficiency (SCID) and Its New Treatment Modalities.

Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire immune cells. Children with this disease are born with an impaired immune system. The child appears healthy but the consequences of the impaired immune system lead to various secondary infections such as meningeal infections and respiratory infections further leading to consolidation, diarrhea, inflammation of skin and other systemic diseases. Severe combined immunodeficiency is also known as "bubble boy disease" or "living in the bubble" syndrome, as in early days for treatment the physicians decided to completely isolate them until they got the perfect match for the bone marrow transplantation. It is one of the pediatric emergencies and is to be treated as soon as possible. SCID involves multiple genes which leads to makes diagnosis of the disease cumbersome. In early years many infants were diagnosed almost after half a year and in severe conditions which led to the decrease in the survival rate of the children. But now due to advanced newborn screening modalities and other monitoring systems it can be diagnosed as early as within three months of age. The various treatment modalities include hematopoietic stem cell transplantation, gene therapy, enzyme replacement therapy and chemotherapy. This narrative review article describes about the severe combined immunodeficiency and its newer treatment modalities.

Specific Clinical and Immunological Changes Following Mesenchymal Stem Cell Transplantation in COVID-19-induced Acute Respiratory Distress Syndrome Patients: A Phase-I Clinical Trial.

Acute respiratory distress syndrome (ARDS) is a systemic inflammation resulting from immune system overactivity. ARDS is also a fatal complication of COVID-19. Mesenchymal stem cells (MSCs) have immune modulatory properties. This study evaluated the safety and efficacy of three times transplantation of umbilical cord-derived MSCs (UC-MSCs) in terms of specific immunological and clinical changes in mild-to-moderate COVID-19-induced ARDS patients. In this single-center, open-label, phase 1 clinical trial, 20 patients diagnosed with COVID-19 and mild-to-moderate ARDS were included and were divided into two groups: a control group receiving standard care and an intervention group receiving UC-MSC in addition to standard care. Three consecutive intravenous transplants of UC-MSC (1×  cells/kg body weight per each transplant) were performed in the intervention group on days 1, 3, and 5. The biological assay was investigated four times (days 0, 5, 10, and 17). UC-MSCs improved the patients' clinical and paraclinical parameters, including leukocytosis, lymphopenia, thrombocytopenia, and liver enzyme abnormalities compared to the control group. They also decreased pro-inflammatory lymphocytes (TH1 and TH17) and increased anti-inflammatory T lymphocytes. Cell therapy also reduced the mean fluorescence intensity (MFI) in overactivated CD8+ T cells.  These findings show that three UC-MSC injections could regulate a hyperactivated immune system in COVID-19-induced ARDS patients by decreasing the inflammatory T lymphocyte subset and can improve the patient's hematological condition and liver function. However, more studies are needed in this area.

Registered human trials addressing environmental and occupational toxicant exposures: Scoping review of immunological markers and protective strategies.

Exposure to pollution is a worldwide societal challenge participating in the etiology and progression of different diseases. However, the scarce information hinders our understanding of the actual level of human exposure and its specific effects. Inadequate and excessive immune responses underlie diverse chronic diseases. Yet, it is unclear which and how toxicant exposures affect the immune system functions. There is a multiplicity of immunological outcomes and biomarkers being studied in human trials related to exposure to different toxicants but still without clear evidence of their value as biomarkers of exposure or effect. The main aim of this study was to collect scientific evidence and identify relevant immunological biomarkers used at the clinical level for toxicant exposures. We used the platform clinical trials.gov as a database tool. First, we performed a search combining research items related to toxicants and immunological parameters. The resulting117 clinical trials were examined for immune-related outcomes and specific biomarkers evaluated in subjects exposed to occupational and environmental toxicants. After categorization, relevant immunological outcomes and biomarkers were identified related to systemic and airway inflammation, modulation of immune cells, allergy and autoimmunity. In general, the immune markers related to inflammation are more frequently investigated for exposure to pollutants, namely IL-6, C-reactive protein (CRP) and nitric oxide (NO). Nevertheless, the data also indicated that prospective biomarkers of effect are gaining ground and a guiding representation of the established and novel biomarkers is suggested for upcoming trials. Finally, potential protective strategies to mitigate the adverse effects of specific toxicants are underlined for future studies.

The Role of Biochemical and Respiratory Markers in the Mortality of Patients With SARS-CoV-2 Infection in a Mexican Population.

BACKGROUND: The SARS-CoV-2 pandemic has challenged the traditional perspectives of health care. The objective of our study was to analyze the association of different hematological biomarkers and respiratory assistance with the disease's severity and mortality in COVID-19. MATERIALS AND METHODS: A single reference center, cross-sectional, retrospective, descriptive and analytical, observational study was carried out on 362 SARS-CoV-2 positive adults from April to October 2020. RESULTS: The mean age of the population was 55.92±13.12 years. A distribution by gender of n=227 (63.0%) men and n=135 women (37.0%) was found. Mortality occurred in 14% of the studied population. Comorbidities associated were hypertension n=128 (35.0%) and diabetes n=112 (31.0%). Of the 362 patients, 64 required advanced ventilatory support when taken to the intensive care unit, of these 39 (60.9%) died and only 25 (39.1%) survived (p<0.0001). On the other hand, biochemical indicators such as CRP, D-dimer, DHL, lymphocytes, leukocytes, neutrophils, and the neutrophil/lymphocyte ratio, showed a significant difference (p<0.0001) at admission and during the stay in the intensive care unit. CONCLUSIONS: Patients who required ventilatory assistance showed an increased risk of mortality, as did those who were admitted to the intensive care unit. Higher mortality was associated with higher values ​​of CRP, DHL, D-dimer, neutrophil/lymphocytes ratio, total leukocytes, and lower lymphocytes.

A glance at the emerging diagnostic biomarkers in the most prevalent genitourinary cancers.

Genitourinary cancers comprise of a heterogenous group of cancers of which renal cell carcinoma, urothelial bladder carcinoma, and prostate adenocarcinoma are the most commonly encountered subtypes. A lot of research is ongoing using various strategies for exploration of novel biomarkers for genitourinary cancers. These biomarkers would not reduce the need for invasive diagnostic techniques but also could be used for early and accurate diagnosis to improve the clinical management required for the disease. Moreover, selecting the appropriate treatment regimen for the responsive patients based on these biomarkers would reduce the treatment toxicity as well as cost. Biomarkers identified using various advanced techniques like next generation sequencing and proteomics, which have been classified as immunological biomarkers, tissue-specific biomarkers and liquid biomarkers. Immunological biomarkers include markers of immunological pathways such as CTLA4, PD-1/PDl-1, tissue biomarkers include tissue specific molecules such as PSA antigen and liquid biomarkers include biomarkers detectable in urine, circulating cells etc. The purpose of this review is to provide a brief introduction to the most prevalent genitourinary malignancies, including bladder, kidney, and prostate cancers along with a major focus on the novel diagnostic biomarkers and the importance of targeting them prior to genitourinary cancers treatment. Understanding these biomarkers and their potential in diagnosis of genitourinary cancer would not help in early and accurate diagnosis as mentioned above but may also lead towards a personalized approach for better diagnosis, prognosis and specified treatment approach for an individual.

Cell-Mediated Immunological Biomarkers and Their Diagnostic Application in Livestock and Wildlife Infected With Mycobacterium bovis.

Mycobacterium bovis has the largest host range of the Mycobacterium tuberculosis complex and infects domestic animal species, wildlife, and humans. The presence of global wildlife maintenance hosts complicates bovine tuberculosis (bTB) control efforts and further threatens livestock and wildlife-related industries. Thus, it is imperative that early and accurate detection of M. bovis in all affected animal species is achieved. Further, an improved understanding of the complex species-specific host immune responses to M. bovis could enable the development of diagnostic tests that not only identify infected animals but distinguish between infection and active disease. The primary bTB screening standard worldwide remains the tuberculin skin test (TST) that presents several test performance and logistical limitations. Hence additional tests are used, most commonly an interferon-gamma (IFN-γ) release assay (IGRA) that, similar to the TST, measures a cell-mediated immune (CMI) response to M. bovis. There are various cytokines and chemokines, in addition to IFN-γ, involved in the CMI component of host adaptive immunity. Due to the dominance of CMI-based responses to mycobacterial infection, cytokine and chemokine biomarkers have become a focus for diagnostic tests in livestock and wildlife. Therefore, this review describes the current understanding of host immune responses to M. bovis as it pertains to the development of diagnostic tools using CMI-based biomarkers in both gene expression and protein release assays, and their limitations. Although the study of CMI biomarkers has advanced fundamental understanding of the complex host-M. bovis interplay and bTB progression, resulting in development of several promising diagnostic assays, most of this research remains limited to cattle. Considering differences in host susceptibility, transmission and immune responses, and the wide variety of M. bovis-affected animal species, knowledge gaps continue to pose some of the biggest challenges to the improvement of M. bovis and bTB diagnosis.

Lymphocyte-Related Immunological Indicators for Stratifying Mycobacterium tuberculosis Infection.

Background: Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC). Methods: A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously. Results: Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%). Conclusions: Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection.

Immunological parameters as biomarkers of response to MicroCrystalline Tyrosine-adjuvanted mite immunotherapy.

BACKGROUND: Despite the effectiveness of allergen immunotherapy (AIT), some patients are unresponsive for reasons still unknown; yet validated response biomarkers remain unavailable. OBJECTIVE: To analyze immunological parameters as biomarkers to monitor and predict clinical response to a MicroCrystalline Tyrosine-adjuvanted house dust mite (HDM) AIT in patients with allergic rhinitis (AR). METHODS: Observational, prospective, multicenter study including adult patients (aged 18-65 years) with AR, with and without asthma, sensitized to the HDM Dermatophagoides pteronyssinus (DP) and prescribed Acarovac Plus® DP 100% in the routine practice. Serum concentrations of total IgE, specific IgE, specific IgG4, IL-4, IL-5, IL-10, IL-13, and IFN-γ were compared between baseline and 12 months after AIT. The relationship between patients' baseline immunological profiles and classification as low, high, and non-responders and between their sensitization profile to DP allergens and effectiveness were analyzed. RESULTS: Of 141 patients recruited, 118 (mean [SD] age of 33.6 [9.5] years) were evaluable. One year after treatment, Der p 1-specific IgE, DP-specific IgG4, and IL-10 increased by a mean (SD) of 3.4 (13.6) kU/L (p = 0.016), 0.43 (0.55) mg/L (p < 0.0001), and 1.35 (7.56) pg/mL (p = 0.033), respectively. Non-responders showed increased baseline levels of IL-13 compared to high responders (p = 0.037). Changes in effectiveness variables between baseline and after AIT were similar regardless of the sensitization profile. CONCLUSION: Non-responsive patients to AIT showed increased baseline IL-13 concentrations, suggesting its value as prognostic biomarker. DP-specific AIT increased Der p 1-specific IgE, DP-specific IgG4, and IL-10 concentrations in patients with AR. All patients benefited from treatment regardless of their sensitization profile to major DP allergens.

The Neuroimmune and Neurotoxic Fingerprint of Major Neurocognitive Psychosis or Deficit Schizophrenia: a Supervised Machine Learning Study.

No studies have examined the immune fingerprint of major neurocognitive psychosis (MNP) or deficit schizophrenia using M1 macrophage cytokines in combination with chemokines such as CCL2 and CCL11. The present study delineated the neuroimmune fingerprint of MNP by analyzing plasma levels of IL-1ß, sIL-1RA, TNFα, sTNFR1, sTNFR2, CCL2, and CCL11 in 120 MNP versus 54 healthy controls in association with neurocognitive scores (as assessed with the Brief Assessment of Cognition in Schizophrenia) and PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. MNP was best predicted by a combination of CCL11, TNFα, IL-1ß, and sIL-1RA which yielded a bootstrapped (n = 2000) area under the receiver operating curve of 0.985. Composite scores reflecting M1 macrophage activity and neurotoxic potential including effects of CCL11 and CCL2 were significantly increased in MNP. A large part of the variance in PHEM (38.4-52.6%) and negative (65.8-74.4%) symptoms were explained by combinations of immune markers whereby CCL11 was the most important. The same markers explained a large part of the variance in the Mini-Mental State examination, list learning, digit sequencing task, category instances, controlled word association, symbol coding, and Tower of London. Partial least squares analysis showed that 72.7% of the variance in overall severity of schizophrenia was explained by the regression on IL-1ß, sIL-1RA, CCL11, TNFα, and education. It is concluded that the combination of the abovementioned markers defines MNP as a distinct neuroimmune disorder and that increased immune neurotoxicity determines memory and executive impairments and PHEMN symptoms as well.