Polyfunctional T Cell and Neutralizing Antibody Responses to ACAM2000TM Smallpox Vaccine Immunization in Primary-Vaccinated Individuals

Smallpox eradication was successful via prophylactic administration of live attenuated vaccinia virus. As a result of the discontinuation of the smallpox immunization program, many individuals are now susceptible to smallpox virus infection should it be used as a biological weapon. Presently, only individuals at high risk for exposure are required to receive smallpox vaccine, such as laboratory personnel that handle variola/vaccinia virus. This study endeavored to investigate a one-year period of vaccinia virus-specific T cell responses using polychromatic flow cytometry and neutralizing (Nt) antibody responses using plaque reduction neutralization test (PRNT) in individuals receiving primary immunization (n = 5) with ACAM2000TM smallpox vaccine. Functional and phenotypic profiles of vaccinia virus-specific T cell responses were characterized. Each single functional measurement {CD107a/b expression, production of interferon g (IFN-g), macrophage inflammatory protein 1b (MIP-1b), interleukin 2 (IL-2), and tumor necrosis factor a (TNF-a)} demonstrated that vaccinia virus-specific CD8+ T cells were functional at least one time point after vaccination (p ≤ 0.05). However, vaccinia virus-specific CD4+ T cells were functional only for MIP-1b production (p ≤ 0.05). Vaccinia virus-specific CD8+ T cells induced in these individuals showed increased polyfunctionality in at least 2 phenotypes relative to pre-vaccination (p ≤ 0.05). Although only three of five individuals (60%) showed positive Nt antibody (titer ≥ 20) at first month after vaccination, all five individuals (100%) demonstrated Nt antibody at 2 months, post-immunization. Interestingly, all vaccinees could retain the Nt antibody for 6 months after primary vaccination. In conclusion, ACAM2000TM smallpox vaccine induced both polyfunctional T cell-and Nt antibody-responses in primary immunized individuals.

Role of autoimmunity in primary biliary cirrhosis

Primary biliary cirrhosis(PBC) is an autoimmune liver disease characterized by the presence of serum autoantibodies and chronic nonsuppurative destructive cholangitis.The pathogenesis of PBC involves environmental factors,genetic predisposition and loss of immune tolerance.In recent years,it has become univocally accepted that an inappropriately activated immune response is one of the most important factors in PBC.In this study,the role of autoimmunity in PBC is summarized and a feasible research orientation is recommended.

Primary Immune Deficiencies (PID): Diagnosis Challenges

Background: Primary Immune Deficiencies (PID) are rare, under-determined diseases particularly in sub-Saharan Africa. The diagnosis is often suspected with uncommon clinical signs. Infections are the main diagnostic circumstances in infants. Confirmation is often difficult because some additional examinations are unavailable in many of our countries. Aim: Our aim was to share the challenge of diagnosis and treatment in PID. Case Presentation: It is about two infants, a boy and a girl, with early several infections. Both of them presented a hypo-gammaglobulinemia and to the boy, the immuno-phenotyping lymphocyte showed a decreased level of lymphocytes CD19. We are looking for genetic confirmation but it is not easy. The treatment of these infants requires a substitution for life of immunoglobulin which is unavailable in our countries. Conclusion: PID are suspected with atypical clinical signs. Confirmation genetic diagnosis is difficult in low income countries. To improve the follow up, we need to strengthen clinical-biological collaboration.

The Cyclic Feeding Regime Induces Decaying Age-Dependent Oxidative Stress and Regulates the Cell Chain of the Immunity

We developed an experimental model of a cyclic feeding regime (CFR) that increased a lifespan in rats. The manifestations of oxidative stress and their interrelation with parameters of cell immunity were assessed in rats at CFR. It is shown that changes of body mass, liver mass and indexes of pro/antioxidant system after periods of starving—ad libitum nutrition at CFR diet in old animals were less pronounced than in young animals. The body mass loss of 30% in 14 days was accompanied by oxidative stress. Indexes of phagocytosis did not change, but activity of oxidase system of neutrophil was increased in 2 times. The response of metabolic and physiological systems on repeat starving—ad libitum nutrition cycles differs from the response to the initial cycle of CFR. This is interpreted as a change of adaptation strategy and the effect of metabolic memory, which influences the choice of organism strategy of adaptation for subsequent starving. The dynamics of change of the studied indexes in response to CFR was age-dependent. It was supposed that different answer to CFR in young and old animals is determined by the different amount of carbon and fat depots in young and old animals.

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

Advances in immunopathogenesis of adult immune thrombocytopenia

Primary immune thrombocytopenia(ITP)is an autoimmune disorder characterized by immune-mediated accelerated platelet destruction and/or suppressed platelet production.Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP,several abnormalities involving the cellular mechanisms of immune modulation have been identified,and the pathways behind the immune-mediated destruction of platelets have opened new avenues for the design of specific immunotherapies in an attempt to reduce the platelet destruction.This review is primarily focused on the recent literature with respect to immunopathological mechanisms in patients with ITP.

Clinical features and follow-up of Chinese patients with symptomatic hypogammaglobulinemia in infancy

Background Hypogammaglobulinemia is common in infant humoral immunodeficiencies and has complicated causes and outcomes. We aimed to determine the clinical manifestations, immunological changes and outcomes of Shanghai infants with hypogammaglobulinemia. Methods Patients under 2 years old, having one or more warning signs of primary immunodeficiency disorders, serum immunoglobulin levels below the lower limit of reference range per age, and with normal numbers for lymphocyte subsets were analyzed and followed up for 2 to 3 years. Results A total of 91 children （male-to-female ratio： 2.25： 1） participated in the study. Initial clinical presentation was recurrent upper respiratory tract infection （46%）, invasive infection （3%）, atopic disease （32%）. IgA reduction （77%） was prevalent; 34% patients had more than one isotype reduced. During follow-up, 51 of 62 patients （82.25%） had immunoglobulins normalized at the age between 12-48 months; these were diagnosed as transient hypogammaglobulinemia of infancy （THI）. Long-term follow-up may reveal a diagnosis for the remaining 11 infants with persistent lower Jmmunoglobulin levels, who did not have antibody titers measured. Earlier onset was correlated with higher rates of normalization. More patients were diagnosed with isolated hypogammaglobulinemia in 2006 compared with the previous 4 years （2002-2005）. Conclusions The awareness of immunodeficiency among pediatricians has been greatly improved. Recurrent otitis media was not a major infection in our patients. THI is a relatively common condition associated with infant hypogammaglobulinemia. In the absence of specific antibody titers, the diagnosis of THI can be confirmed retrospectively with Ig levels normalized in follow-up visits. Therefore, long-term follow-up and frequent re-evaluation of these patients are necessary to distinguish them from true primary immunodeficiency.