T-lymphocyte Dysfunction Research Articles

Abstract We077: Mechanisms of T-lymphocyte Dysfunction in Dilated Cardiomyopathy Patients

Preclinical studies have shown that T-cells infiltrate the heart during heart failure (HF), promoting remodeling. However, it remains unclear whether activated T-cells infiltrate the human failing hearts also. Importantly, cellular mechanisms that are involved in T-cell activation during human HF are unknown. To address this question, we analyzed published single-cell RNA sequencing data from patients with dilated cardiomyopathy (DCM) and compared it with control hearts. Our analysis focused on characterizing the gene expression of cardiac T-cells to uncover potential mechanisms underlying their role in human HF. We found that patients with DCM had significantly more cardiac CD3+ T-cells (%CD45+ cells; 35.5±5.9 vs 22.0±0.8 p < 0.01), with gene signatures indicative of higher TCR dependent antigenic activation, proliferation, and exhaustion. Although there were no differences in the proportion of CD4+ helper and CD8+ cytotoxic T-cells between groups, patients with DCM had a higher proportion of activated (%CD45+ cells, 6.6±0.8 vs 3.1±0.3 p = 0.03) and proliferative CD4+ T-cells (%CD45+ cells, 8.0±0.8 vs 3.1±0.3 p < 0.01). Additionally, genes involved in TNF and TGFβ signaling were significantly enriched in cardiac T-cells derived from patients with DCM (normalized enrichment scores = 2.35, p adj < 0.01, and 1.72, p adj < 0.01, respectively),consistent with preclinical studies published by us and others. Recently, we also showed that dysfunctional T-cells exhibit increased estrogenic signaling with activation of Estrogen Receptor (ER)α in mice. Thus, we also looked at estrogen signaling in T-cells infiltrated into the DCM hearts and found that, indeed, cardiac T-cells in DCM patients exhibit significant upregulation of genes involved in estrogen signaling (normalized enrichment score = 1.69, p adj < 0.01). This comprehensive analysis, for the first time, shows that T-cells are antigenically activated, actively infiltrate the failing human hearts and exhibit increased estrogenic signaling during DCM, providing novel insights and potential avenues for targeted immunotherapies.

#2367 Membranoproliferative glomerulonephritis preceding non-Hodgkin lymphoma recurrence : a case report

Abstract Background and Aims Glomerulonephritis (GN) have been known to be associated with both chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Membranoproliferative Glomerulonephritis (MPGN) is the most commonly reported histological diagnosis in these diseases. Method This report presented a rare case of membranoproliferative glomerulonephritis preceding non- Hodgkin lymphoma recurrence. Results In September 2023, we report the case of a 75-year-old woman with Sjögren's syndrome, systemic lupus erythematosus and hypertension history. Two years prior, she developed non Hodgkin lymphoma requiring chemotherapy with cyclophosphamide, prednisone, rituximab, and vincristine. It has remained in remission. She was admitted to our department with peripheral edema complaint. Physical examination showed edema in the lower extremities. The blood pressure was 130/85 on her antihypertensive regimen. No lymphadenopathies were found. She had mild proteinuria, microhematuria and reduced estimated glomerular filtration rate. The serum creatinine level was 190 µmol/l. She had 1.8 gr/day proteinuria. Laboratory data showed decreased levels of serum C3, C4. Anti-nuclear antibody (ANA) screens were negative. The cryoglobulins test was negative. Hepatitis B, hepatitis C, and HIV serologies were negative. Renal biopsy was performed and resulted as membranoproliferative glomerulonephritis with positive IgM immunofluorescence stain (Figs 1 and 2). We therefore concluded to a membranoproliferative glomerulonephritis with monotypic immunoglobulin deposits. After investigations, she got recurrent non-Hodgkin lymphoma diagnosis. Discussion GN may precede, coexist, or follow the diagnosis of lymphoma by several years. The pathogenesis of paraneoplastic GN remains uncertain, although autoimmune mechanisms and T-lymphocyte dysfunction may be important in this respect. Conclusion Secondary membranoproliferative glomerulonephritis can be observed in non-Hodgkin lymphoma patients but there are few reports about clinical results of lymphoma treatment. There is limited information available concerning the effects of treatment of non-Hodgkin's lymphoma on the progression of non-Hodgkin's lymphoma associated membranoproliferative glomerulonephritis.

Leptin antagonism attenuates hypertension and renal injury in an experimental model of autoimmune disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by B- and T-lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin has various immunomodulatory properties, including promoting the expansion of proinflammatory T lymphocytes and the proliferation and survival of B cells. In the present study, we hypothesized that leptin antagonism would improve B- and T-cell dysfunction and attenuate hypertension in an experimental model of SLE, the NZBWF1 mouse. To test this hypothesis, 28-week-old female control and SLE mice were administered 5 mg/kg of murine leptin superantagonist (LA) or vehicle via ip injection every other day for four weeks. Analysis of peripheral blood immune cell populations showed no changes in total CD45R+ B and CD3+ T cell percentages after treatment with LA. However, SLE mice treated with LA had an improved CD4/CD8 ratio and decreased CD3+CD4-CD8- double negative (DN) T cells. Blood pressure was higher in SLE than in control, and treatment with LA decreased blood pressure in SLE mice. Treatment with LA also delayed the onset of albuminuria and decreased glomerulosclerosis in SLE mice. Renal immune cell infiltration was significantly higher in SLE mice as compared with control, but LA treatment was associated with decreased levels of renal CD4+ T cells. In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in SLE, in part, by promoting the expansion of inflammatory DN T cells and the infiltration of T cells into the kidneys.

1947. Evaluating the Relationship Between Obesity and the Humoral Immune Response to COVID-19 Vaccines

Abstract Background The pro-inflammatory state associated with obesity leads to B- and T-lymphocyte dysfunction that may lead to an inadequate immune response to natural infection and vaccination. Preliminary studies, conducted outside of the US, involving multiple COVID-19 vaccines indicate that obesity may impact antibody response. The objective of this study was to evaluate the role of inflammatory status as a mediator in the relationship between obesity and COVID-19 vaccine immune response in a predominantly African-American population. Methods This cross-sectional analysis involved 54 participants ≧ 18 years of age who had completed the primary dosing schedule and booster for Novavax’s recombinant COVID-19 vaccine, NVX-CoV2373. Weight, height, and waist circumference (WC) measurements were taken. Medical history including COVID-19 vaccination and known COVID-19 infection were obtained. Blood samples were taken for measurement of c-reactive protein (CRP) and anti-SARS-CoV-2 spike protein IgG levels. Spearman correlation coefficient was used to assess the presence of a relationship between BMI and CRP, WC and CRP, CRP and spike protein IgG, BMI and spike protein IgG, and finally, WC and spike protein IgG. Mediation analysis was used to evaluate the moderating effect of plasma CRP on the relationship between WC and spike protein IgG while adjusting for suspected confounders. Statistical significance was defined as p < .05. Results There was an expected positive relationship between WC and CRP, (ρ = 0.37, p< .05). CRP and spike protein IgG trended towards a weak, negative relationship (ρ= -0.13, p > .05). WC and BMI both trended towards a positive relationship with anti-SARS-CoV-2 spike protein IgG (ρ = 0.29 and 0.15, respectively, p >.05). The mediation analysis showed that WC positively influenced spike protein IgG (p< .05), and this effect was not mediated by CRP. Conclusion Inflammation may be negatively associated with antibody response to COVID-19 vaccines. WC and antibody response may be positively related in NVX-CoV2373 recipients, in spite of chronic low-grade inflammation. Further research is needed to fully characterize the impact of obesity on COVID-19 vaccine immunogenic responses. Disclosures Lilly Immergluck, MD, MS, GSK: Clinical Trial- PI|Merck: Vaccine Trial Site- serve as PI|Moderna: Board Member|Novavax: Part of CoVID-19 Phase 3 Trial through US Covid Prevention Network.

Lung cancer and HIV

BACKGROUND: People, living with HIV, have a greater chance of malignancies especially with the success of antiretroviral therapy, and non-AIDS-defining cancers have become the most common cause of death after AIDS and the most common of them is the lung cancer in developed countries.
 AIM: To research nosological characteristics of lung cancer in the context of HIV infection, HIV-associated risk factors during antiretroviral therapy and compare with global trends of this problem.
 MATERIALS AND METHODS: Retrospectively were analyzed the medical documentation of 98 patients with lung cancer and HIV-infection, who were in database and received specialized treatment in Saint Petersburg from 2008 to 2018 years.
 RESULTS: The population was dominated by patients of young (1844 years old) and middle (4559 years old) ages, 45.9% and 42.9%, respectively, and 11.2% of elderly patients (6074 years old), p 0.001, which satisfies the global data of earlier incidence of lung cancer in people living with HIV.
 Adenocarcinomas were more common histological subtype of lung cancer as in the general population (p 0.001).
 There was no static significance between high viral load and lung cancer, which can indicate the absence of a direct mechanism of HIV-carcinogenesis (90.8% of patients with low and medium viral load, p 0.001). Nevertheless, the prevalence of 4-stage of HIV infection among lung cancer patients (p 0.001) indicates a history of inflammatory diseases, including pulmonary diseases, as a result of induced immunosuppression due to CD8+-lymphocyte dysfunction and the formation of a micro-tumor environment, which can be a prognostic unfavorable factor in the occurrence of lung cancer in this group of patients , as well as indirect mechanism of viral carcinogenesis.
 The presence of elderly patients (11.2%, MAX71 years) indirectly indicates an increasing of period of life expectancy among this category of patients in Russia.
 CONCLUSION: The mechanisms of increased risk of lung cancer among HIV-infected people remain largely unclear and can be the area for active research. HIV-infected patients with lung cancer are younger than HIV-negative patients and have more advanced stages of cancer with a prevalence of adenocarcinoma type of cancer. The lung cancer prognosis of survival in HIV-infected people is much worse than that of persons without HIV-infection, but it is not fully known whether this is due to a more aggressive course of the disease, disparities in treatment, treatment resistance, or a greater risk and toxicity of therapy.

Innate lymphocytes: Role in alcohol-induced immune dysfunction.

Alcohol use is known to alter the function of both innate and adaptive immune cells, such as neutrophils, macrophages, B cells, and T cells. Immune dysfunction has been associated with alcohol-induced end-organ damage. The role of innate lymphocytes in alcohol-associated pathogenesis has become a focus of research, as liver-resident natural killer (NK) cells were found to play an important role in alcohol-associated liver damage pathogenesis. Innate lymphocytes play a critical role in immunity and homeostasis; they are necessary for an optimal host response against insults including infections and cancer. However, the role of innate lymphocytes, including NK cells, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, gamma delta T cells, and innate lymphoid cells (ILCs) type 1–3, remains ill-defined in the context of alcohol-induced end-organ damage. Innate-like B lymphocytes including marginal zone B cells and B-1 cells have also been identified; however, this review will address the effects of alcohol misuse on innate T lymphocytes, as well as the consequences of innate T-lymphocyte dysfunction on alcohol-induced tissue damage.

Screening Method for 22q11 Deletion Syndrome Involving the Use of TaqMan qPCR for TBX1 in Patients with Conotruncal Congenital Heart Disease

22q11.2 deletion syndrome is a phenotypic spectrum that encompasses DiGeorge syndrome (OMIM: 188400) and velocardiofacial syndrome (OMIM: 192430). It is caused by a 1.5–3.0 Mb hemizygous deletion of locus 22q11.2, which leads to characteristic facies, conotruncal cardiovascular malformations, velopharyngeal insufficiency, T-lymphocyte dysfunction due to thymic aplasia, and parathyroid hypoplasia, and, less frequently, neurological manifestations such as delayed psychomotor development or schizophrenia. This study aimed to describe a screening method for the diagnosis of 22q11.2 deletion syndrome in patients with Conotruncal Congenital Heart Disease (CCHD), using qPCR to detect the copy number of the TBX1 gene in a single DNA sample. A total of 23 patients were included; 21 with a biallelic prediction of the TBX1 copy number gene and 2 with a monoallelic prediction who were suspected to be positive and subjected to MLPA confirmation. One patient (4.34%) with truncus arteriosus CCHD was confirmed to have 22q11.2 deletion syndrome. We propose this approach as a possible newborn screening method for 22q11.2 deletion syndrome in CCHD patients.

Reprogrammed CD8+ T-Lymphocytes Isolated from Bone Marrow Have Anticancer Potential in Lung Cancer.

CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors and PD-1 blockers to increase their antitumor activity. Antitumor effects of reprogrammed T-lymphocytes were shown in vitro and in vivo in the Lewis lung carcinoma model. The population of T- lymphocytes with persistent expression of CCR7 was formed as a result of reprogramming. Reprogrammed T-lymphocytes were resistant to apoptosis and characterized by high cytotoxicity against Lewis lung carcinoma (LLC) cells in vitro. Administration of reprogrammed T-lymphocytes to C57BL/6 mice with LLC reduced the number of lung metastases. The antitumor effect resulted from the elimination of tumor cells and cancer stem cells, and the effect of therapy on cytotoxic T-lymphocyte counts. Thus, reprogramming of T-lymphocytes using MEK inhibitors is a promising approach for targeted therapy of lung cancer.

Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome.

Studies concerning the role of arachidonic acid (AA) and its metabolites in kidney disease are scarce, and this applies in particular to idiopathic nephrotic syndrome (INS). INS is one of the most frequent glomerular diseases in childhood; it is characterized by T-lymphocyte dysfunction, alterations of pro- and anti-coagulant factor levels, and increased platelet count and aggregation, leading to thrombophilia. AA and its metabolites are involved in several biological processes. Herein, we describe the main fields where they may play a significant role, particularly as it pertains to their effects on the kidney and the mechanisms underlying INS. AA and its metabolites influence cell membrane fluidity and permeability, modulate platelet activity and coagulation, regulate lymphocyte activity and inflammation, preserve the permeability of the glomerular barrier, influence podocyte physiology, and play a role in renal fibrosis. We also provide suggestions regarding dietary measures that are able to prevent an imbalance between arachidonic acid and its parental compound linoleic acid, in order to counteract the inflammatory state which characterizes numerous kidney diseases. On this basis, studies of AA in kidney disease appear as an important field to explore, with possible relevant results at the biological, dietary, and pharmacological level, in the final perspective for AA to modulate INS clinical manifestations.

Successful Treatment of Vitiligo with Cold Atmospheric Plasma‒Activated Hydrogel

Vitiligo shows insufficient response to current therapies largely owing to T-lymphocyte dysfunction, abnormal inflammatory activation, and excessive oxidative stress in lesions. Cold atmospheric plasma (CAP) possesses pleiotropic antioxidant and anti-inflammatory properties and may offer an improvement to current treatment options. In this study, the efficacy and safety of CAP were investigated in a mouse model of vitiligo and a randomized and controlled trial of patients with active focal vitiligo. Skin biopsies showed that topical treatment of vitiligo-like lesions on mouse dorsal skin by CAP restored the distribution of melanin. In addition, CAP treatment reduced the infiltration of CD11c+ dendritic cells, CD3+ T cells, and CD8+ T cells; inhibited the release of CXCL10 and cytokine IFN-γ; and enhanced cellular resistance to oxidative stress and excessive immune response by enhancing the expression of the transcription factor NRF2 and attenuating the activity of inducible nitric oxide synthase. In a randomized and controlled trial, CAP treatment achieved partial and complete repigmentation in 80% and 20% of vitiligo lesions, respectively, without hyperpigmentation in surrounding areas or other adverse events during the treatment period and its follow-up period. In conclusion, CAP offers a promising option for the management of vitiligo.

Investigation of regulation and mechanism of miR-223 on autophagy of CD4 + T lymphocytes in septic mice

T-lymphocyte dysfunction is most important part of immune dysfunction in sepsis, where dynamic change, especially autophagy of CD4+T lymphocytes is found to be related to disease fate. Our study is to i nvestigate the changes of CD4 + T lymphocytes and their autophagy levels in septic miR-223 −/− mouse model injected intraperitoneally with E. coli.120 male C57BL/6J wild-type. Twenty male miR-223 knockout(miR-223-/-) mice were randomly divided into, according to intraperitoneal injection of normal saline (NS) and E. coli solution, normal saline (WT NS) group, sepsis (WT Sep) group, miR-223 −/− NS group and miR-223 −/− Sep group, respectively. The autophagy related protein was monitored with flow cytometry to observe the autophagy of CD4+T lymphocytes. Flow cytometry showed the proportion of CD4 + T lymphocytes in peripheral blood circulation, alveoli, and spleen of mice in the WT Sep group gradually decreased after surgery, the proportion of cells with autophagic activity in this population of cells was significantly higher than that in the WT NS group, and the proportion of CD4 + T lymphocytes with active autophagic activity in miR-223 −/− mice were significantly decreased, but higher than that in the miR-223 −/− NS group and lower than the level of autophagy in CD4 + T cells of wild-type mice. Thus, miR-223 can up-regulate the level of autophagy in CD4 + T lymphocytes of septic mice, suggesting that miR-223 may be used as a potential target for the prevention and treatment of sepsis.

Targeting Lymphocyte Activation Gene 3 to Reverse T-Lymphocyte Dysfunction and Improve Survival in Murine Polymicrobial Sepsis.

Lymphocyte activation gene 3 (LAG-3) is one of the immune checkpoint molecules, negatively regulating the T-cell reactions. The present study investigated the role of LAG-3 in sepsis-induced T-lymphocyte disability. Mice sepsis was induced by cecal ligation and puncture (CLP). LAG-3 expression on some immune cells were detected 24 hours after CLP. LAG-3 knockout and anti-LAG-3 antibody were applied to investigate the effects on the survival, bacterial clearance. Cytokine levels, T-cell counts, and the presence of apoptosis (in blood, spleen, and thymus) were also determined. In vitro T-cell apoptosis, interferon γ secretion, and proliferation were measured. The expression of interleukin 2 receptor on T cells was also determined after CLP. LAG-3 was up-regulated on CD4+/CD8+ T, CD19+ B, natural killer, CD4+CD25+ regulatory T cells and dendritic cells. Both LAG-3 knockout and anti-LAG-3 antibody had a positive effect on survival and on blood or peritoneal bacterial clearance in mice undergoing CLP. Cytokine levels and T-cell apoptosis decreased in anti-LAG-3 antibody-treated mice. Induced T-cell apoptosis decreased, whereas interferon γ secretion and proliferation were improved by anti-LAG-3 antibody in vitro. Interleukin 2 receptor was up-regulated on T cells in both wild-type and LAG-3-knockout mice undergoing CLP. LAG-3 knockout or anti-LAG-3 antibody blockade protected mice undergoing CLP from sepsis-associated immunodysfunction and may be a new target for the treatment.

Epigallocatechin-3 Gallate Inhibits STAT-1/JAK2/IRF-1/HLA-DR/HLA-B and Reduces CD8 MKG2D Lymphocytes of Alopecia Areata Patients.

Background: Alopecia areata (AA) is associated with Interferon- γ (IFN-γ) mediated T-lymphocyte dysfunction and increased circulating Interleukine-17 (IL-17) levels. Epigallocatechin-3-gallate (EGCG) specifically inhibits IFN-γ pathways and unlike Janus Kinase 1 and 2 (JAK1/JAK2) inhibitors (tofacitinib, ruxolitinib), EGCG is safer, more cost-effective, and is a topically active agent. Our objective is to test the mode of action of EGCG in vitro and ex vivo using HaCat, Jurkat cell lines, and peripheral blood mononuclear cells (PBMCs) of AA patients and healthy controls (HCs), respectively. Methods: distribution of T helper cells (Th1, Th17), and cytotoxic cells (CD8) in PBMCs isolated from 30 AA patients and 30 HCs was investigated by flowcytomterty. In vitro treatment of HaCat and Jurkat cells with 40 μm EGCG for 48 h was performed to measure the level of phosphorylation of signal transducer and activator of transcription protein STAT1, and replicated in ex vivo model using PBMCs of AA patients. Results: Interestingly, 40 μm EGCG is capable of completely inhibiting phosphorylation of STAT1 after 48 h in HaCat and Jurkat cells and ex vivo in PBMCs of AA patients. Based on QPCR data, the action of EGCG on p-STAT1 seems to be mediated via downregulation of the expression of JAK2 but not JAK1 leading to the inhibition of human leukocyte antigens (HLA-DR and HLA-B) expression probably via IRF-1. On the other hand, AA patients have significantly increased levels of Th1, Th17, and CD8 cells and the production of IFN-γ and IL-17 by PBMCs in AA patients was significantly higher compared to HC; p = 0.008 and p = 0.006, respectively. Total numbers of CD8+ cells were not significantly different between treated and untreated samples. However, CD8+ cells with positive Natural killer group 2 member D (NKG2D) transmembrane receptor (CD8+ NKG2D+ subset) was significantly reduced when PBMCs were treated with 20 μm EGCG for 48 h. Conclusion: These results suggest that EGCG has a synergistic action that inhibits expression of HLA-DR and HLA-B molecules via the IFN-γ pathway to maintain immune privilege in HF; also it reduces CD8+ NKG2D+ subset.

Defective T-Cell Apoptosis and T-Regulatory Cell Dysfunction in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease that mostly affects small and large synovial joints. At the molecular level, RA is characterized by a profoundly defective innate and adaptive immune response that results in a chronic state of inflammation. Two of the most significant alterations in T-lymphocyte (T-cell) dysfunction in RA is the perpetual activation of T-cells that result in an abnormal proliferation state which also stimulate the proliferation of fibroblasts within the joint synovial tissue. This event results in what we have termed “apoptosis resistance”, which we believe is the leading cause of aberrant cell survival in RA. Finding therapies that will induce apoptosis under these conditions is one of the current goals of drug discovery. Over the past several years, a number of T-cell subsets have been identified. One of these T-cell subsets are the T-regulatory (Treg) cells. Under normal conditions Treg cells dictate the state of immune tolerance. However, in RA, the function of Treg cells become compromised resulting in Treg cell dysfunction. It has now been shown that several of the drugs employed in the medical therapy of RA can partially restore Treg cell function, which has also been associated with amelioration of the clinical symptoms of RA.

Evaluation and Treatment of Monogenic Forms of Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs) are complex disorders that develop in genetically susceptible hosts due to dysregulated immune responses to microbial dysbiosis and environmental changes. Although in the vast majority of cases, the genetic contribution to development of these diseases is small, in rare cases, IBD develops directly as a result of deleterious mutations in the genes involved in immune and epithelial cell function. In these cases, intestinal inflammation is usually severe, which develops in most cases in the first years of life and occasionally is accompanied by recurrent or atypical infections. In this review, the approach to different monogenic disorders that cause IBD is discussed, including mutations in the IL-10 pathway, neutrophil defects, regulatory T-cell disorders, autoinflammatory conditions, epithelial cell diseases, and disorders affecting B- and T-lymphocyte dysfunction. Moreover, a multidisciplinary diagnostic approach is suggested, which highlights in which cases a monogenic disorder should be suspected. This review contains 3 figures, 3 tables, and 42 references. Key Words: inflammatory bowel disease, IL-10, chronic granulomatous disease, common variable immune deficiency, epithelial cells, genetics, immune cells, mucosal homeostasis, pathogenesis, very early–onset disease.

Evaluation and Treatment of Monogenic Forms of Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBDs) are complex disorders that develop in genetically susceptible hosts due to dysregulated immune responses to microbial dysbiosis and environmental changes. Although in the vast majority of cases, the genetic contribution to development of these diseases is small, in rare cases, IBD develops directly as a result of deleterious mutations in the genes involved in immune and epithelial cell function. In these cases, intestinal inflammation is usually severe, which develops in most cases in the first years of life and occasionally is accompanied by recurrent or atypical infections. In this review, the approach to different monogenic disorders that cause IBD is discussed, including mutations in the IL-10 pathway, neutrophil defects, regulatory T-cell disorders, autoinflammatory conditions, epithelial cell diseases, and disorders affecting B- and T-lymphocyte dysfunction. Moreover, a multidisciplinary diagnostic approach is suggested, which highlights in which cases a monogenic disorder should be suspected. This review contains 3 figures, 3 tables, and 42 references. Key Words: inflammatory bowel disease, IL-10, chronic granulomatous disease, common variable immune deficiency, epithelial cells, genetics, immune cells, mucosal homeostasis, pathogenesis, very early–onset disease.

BTLA as a biomarker and mediator of sepsis-induced immunosuppression

Recent research indicates that T-lymphocyte dysfunction may contribute to sepsis-associated morbidity and mortality. B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor expressed by T lymphocytes and B lymphocytes that is important in regulating lymphocyte activation during inflammation and infection. Shubin and colleagues report that higher mean BTLA expression in critically ill patients may have value in identifying patients with infection. Further studies provide evidence that BTLA activation contributes to T-lymphocyte apoptosis during sepsis. Although this study will require follow-up and further investigation, the results advance current knowledge regarding potential mechanisms underlying sepsis-induced immunosuppression and identify BTLA as a candidate biomarker and mediator of T-cell dysfunction during sepsis.

Safety of saxagliptin: rationale for and design of a series of postmarketing observational studies

To describe the design and rationale of a series of postmarketing studies to examine the safety of saxagliptin, an oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus, in real-world settings. We are conducting a series of retrospective cohort studies using two UK (General Practice Research Database, and The Health Improvement Network) and two US (Medicare, HealthCore Integrated Research Database(SM) ) data sources. The primary outcomes of interest will include (i) hospitalization with acute liver failure, (ii) hospitalization for acute kidney injury, (iii) hospitalization for severe hypersensitivity reactions, (iv) hospitalization for severe infections, (v) hospitalization with infections associated with T-lymphocyte dysfunction (i.e., herpes zoster, tuberculosis, or nontuberculous mycobacteria), and (vi) major cardiovascular events. Diagnosis codes for the outcomes of interest will be validated by medical record review within each data source. Projected use and estimated incidence rates of outcomes of interest suggest there will be at least 80% statistical power to detect a minimum hazard ratio of 1.5 for major cardiovascular events, 2.0 for acute kidney injury and severe infections, 2.4 for acute liver failure, and 4.0 for severe hypersensitivity reactions. Forthcoming. This postmarketing safety assessment will provide important information regarding the safety of saxagliptin and could potentially identify important dipeptidyl peptidase-4 inhibitor class effects. The methods described may be useful to others planning similar evaluations.

Modulation of human T‐cell functions by reactive nitrogen species

Previous studies have suggested that T-lymphocyte dysfunction might be attributable to nitrative stress induced by reactive nitrogen species (RNS). In this manuscript, we explored this hypothesis and provided a direct demonstration of the inhibitory effects of RNS on human T-cell signaling, activation, and migration. We found that short exposure of human T cells to RNS induced tyrosine phosphorylation of several proteins, including the CD3ζ chain of the TCR complex, and release of Ca2+ from intracellular stores. When the exposure to RNS was prolonged, T cells became refractory to stimulation, downregulated membrane receptors such as CD4, CD8, and chemokine receptors, and lost their ability to migrate in response to chemokines. Since substantial protein nitration, a hallmark of nitrative stress, was observed in various human cancers, intratumoral generation of RNS might represent a relevant mechanism for tumor evasion from immune surveillance.

Anti‐cytokine autoantibodies explain some chronic mucocutaneous candidiasis

have offered elegant explanations of whyCMC occurs in APECED: high-titer, neutra-lizing autoantibodies to the T-cell cytokinesthat regulate mucosal antibacterial and anti-fungal activity, IL-17 and IL-22. These cyto-kines were good targets for involvementin CMC: STAT3-deficient hyper IgE (Job’s)syndrome,