Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Studies on human thyroxine-binding globulin (TBG). I. Purification of TBG and immunologic studies on the relationship between TBG from normal persons and those with TBG "deficiency".

A method for obtaining highly purified thyroxine-binding globulin (TBG) from whole human serum is presented. The method employs relatively simple procedures of step-wise ammonium sulfate precipitation followed by column chromatography on DEAE cellulose and DEAE Sephadex. The final product produces a single protein band on disc electrophoresis. The sedimentation constant of the TBG thus purified is 3.91 and its calculated mol wt is 54,000. An antiserum to the highly purified TBG produced a single arc on immunoelectrophoresis. When the antiserum was reacted against normal human serum or against serum from subjects deficient in TBG, each produced two arcs-one identical with that produced by the antigen alone. The second arc is probably the result of a contaminating protein in the antigen, present in too low a concentration to be detectable by disc gel electrophoresis. It is concluded that some persons with TBG "deficiency" have a circulating protein, immunologically indistinguishable from TBG, which is defective in its ability to bind thyroxine.

The metabolism of IgE in patients with immunodeficiency states and neoplastic conditions.

Serum IgE concentrations were determined and IgE turnover studies were performed in control individuals as well as in patients with several disease states. Patients with common variable hypogammaglobulinemia, thymoma and hypogammaglobulinemia, ataxia telangiectasia, and selective IgA deficiency had significantly decreased mean serum IgE concentrations. In turnover studies, this was found to be due to decreased IgE synthesis. In spite of these depressed mean values, some patients with common variable hypogammaglobulinemia had normal serum IgE concentrations and synthetic rates. Patients with the Wiskott-Aldrich syndrome had a significantly elevated mean serum IgE concentration. In one of four patients studied with the turnover technique, a strikingly high IgE concentration was present and was associated with an elevated IgE synthetic rate. Three other patients had both normal serum IgE concentrations and synthetic rates. Patients with chronic lymphocytic leukemia had significantly decreased mean serum concentrations and synthetic rates for IgE. The depressed IgE synthesis was associated with a significantly prolonged IgE half-life. Patients with Hodgkin's disease had significantly increased serum IgE concentrations. One of three patients studied had a high serum IgE concentration and synthetic rate of IgE. The two other patients had normal serum IgE concentrations associated with normal synthetic rates. Finally patients with protein-losing enteropathy or familial hypercatabolic hypoproteinemia had normal IgE concentrations associated with normal IgE metabolic parameters. In these cases, the disorder in the catabolic rate was not severe enough to affect the total amount of circulating IgE because IgE normally has a very high fractional catabolic rate. In general, IgE levels in a variety of disease states were correlated with IgE synthetic rates and abnormalities in the catabolic rate of IgE in disease did not exert an important effect on IgE concentration.

Depression of neutrophil function followed by severe infection in a child with Marasmic Kwashiorkor.

Malnutrition in childhood continues to be one of the most important risk factor for secondary immunodeficiency in the world; therefore one should think of existence of malnutrition in a child suffering of frequent infections, not only in developing country, rarely but still possible in developed country also. Undernourishment in the early childhood is a trigger for starting a vicious cycle of impaired immunity, recurrent infections, and worsening malnutrition. Taking out from that cycle is an urgent and complex process, in which in parallel the infection should be controlled and the nutritional status solved out, and then, slowly follows the restoration of the immune system. We present a patient at the age of 13 months, with marasmic kwashiorkor accompanied by severe infection manifested with sepsis. The laboratory investigations revealed severe anaemia, hypoproteinemia and impaired immunological response, first of all neutrophil dysfunction with decreased oxidative metabolic response during the phagocytosis, paralyzed first line of defense of the organism and open possibility for bacterial or fungal invasion, multiorgan failure and high risk for fatal outcome. Because malnutrition and infections had many causes, only multiple and synergistic interventions embedded in true multisectoral programs, fortunately, were effective and got positive outcome.

Pregnant Woman Bitten by a Japanese Mamushi (Gloydius blomhoffii).

We herein report the fourth case of a pregnant woman bitten by a mamushi. A 33-year-old pregnant woman in the 25th week of gestation was bitten by a mamushi. Her vital signs were stable; however, biochemical analyses of the blood showed mild deterioration of anemia and hypoproteinemia. The effects of envenomation were limited to the extremities, the administration of supportive therapy without antivenom fortunately resulted in a favorable outcome. As there are differences in the maternal medical condition and weeks of gestation, further research is needed to clarify the optimal management strategy for administering antivenom in pregnancy.

Spontaneous remission of hypertrophic lymphocytic gastritis associated with hypoproteinemia.

A 54-year-old woman came to our office because of pretibial edema. She had no gastrointestinal symptoms. Laboratory tests revealed severe hypoproteinemia. Upper gastrointestinal endoscopy demonstrated enlarged gastric folds and multiple aphthoid nodules on the body and the fornix of the stomach. The biopsy specimen revealed a large number of CD8 positive intraepithelial T-lymphocytes infiltrating the gastric mucosa. Both serum total protein and the gastric lesions improved eight months after her first visit without any therapy for peptic ulcer or eradication of Helicobacter pylori. The data suggest that spontaneous remission may occur in lymphocytic gastritis without any gastrointestinal symptoms.

Co-administration of l-cystine and l-theanine enhances efficacy of influenza vaccination in elderly persons: nutritional status-dependent immunogenicity.

AIM: The immune response to influenza vaccine is attenuated in elderly persons, though they are at greatest risk for morbidity and mortality by influenza virus infection. Experimental studies demonstrate that co-administration of l-cystine and l-theanine enhanced antigen-specific production of immunoglobulin in aged mice infected with influenza virus. We thus investigated the effect of l-cystine and l-theanine on antibody induction by influenza vaccines in elderly persons. METHODS: Residents in a nursing home were randomly allocated to l-cystine and l-theanine (n = 32) or placebo (n = 33). The test substances were administered p.o. for 14 days before immunization. Serum influenza virus antibody titers were measured before and 4 weeks after vaccination. RESULTS: Vaccination significantly elevated hemagglutination inhibition (HI) titers for all the three strains of influenza viruses (A/New Caledonia [H1N1], A/New York [H3N2] and B/Shanghai) in both groups. HI titers after vaccination were not significantly different between the two groups for either strain. Also, the seroconversion rate was not significantly different between the two groups in the aggregate. A stratified analysis showed that the rate of seroconversion was significantly greater in the l-cystine and l-theanine group compared with the placebo group for influenza virus A (H1N1) among subjects with low serum total protein (63% vs 10%, P < 0.05) or low hemoglobin (71% vs 9%, P < 0.05). CONCLUSION: Co-administration of l-cystine and l-theanine before vaccination may enhance the immune response to influenza vaccine in elderly subjects with low serum total protein or hemoglobin.

Hypoproteinemia in severe childhood atopic dermatitis: a serious complication.

As a complication of atopic dermatitis (AD), the incidence of hypoproteinemia is increasing among infants with severe AD in Japan. It can be a life-threatening condition owing to hypovolemic shock as a result of hypoproteinemia and vascular infarction as a result of thrombocythemia. However, the pathophysiology of this condition remains unclear. The objectives of the present study were two-fold. The first objective was to determine the main route of protein loss, i.e. through the damaged skin or the gastrointestinal tract, or as a result of insufficient food intake. The second objective was to identify whether allergy or infection was the cause of severe skin inflammation. Fifteen patients with AD were enrolled who had serum protein levels of 3.2-5.8 g/dl. Specific immunoglobulin E (IgE) and skin test to allergens, stool eosinophils, alpha1-antitrypsin clearance, skin Staphylococcus aureus colonization and superantigens (SAgs) produced by the organism, serum SAg-specific IgE antibodies, serum interleukin (IL)-5, IL-6, IL-12, and interferon-gamma (IFN-gamma) were evaluated. Prominent serous skin discharge was seen in all of the patients and was found to have almost the same protein concentration as serum. Marked thrombocytosis, with a maximum of 1,060 x 103/ml, was seen. Skin culture revealed S. aureus colonization in all patients. SAg-producing S. aureus were found in 84.6% of the patients. The concentration of serum IL-5 was significantly increased and correlated well with the blood eosinophil count. Hence, the main route of protein loss was believed to be through damaged skin. The cause of severe inflammation was thought to be a combination of allergic inflammation and skin colonization by SAg-producing S. aureus. Serum cytokines showed a T helper 2 (Th2) T-cell-mediated pattern. To prevent hypovolemic shock, vascular occlusion, and growth retardation, it is of vital importance to diagnose hypoproteinemia at an early stage and start appropriate therapy.

Concanavalin A-induced suppressor cell activity in lipoid nephrosis.

Suppressor cell activity (SCA) was analysed in 28 patients with lipoid nephrosis (LN) and 11 patients with chronic proliferative glomerulonephritis (CGN). We have assessed the ability of peripheral blood lymphocytes (PBL) stimulated by concanavalin A (Con A) to inhibit the proliferative response of normal allogeneic lymphocytes by both Con A and phytohaemagglutinin (PHA). It was found that the LN patients in the earlier phase of relapse had significantly increased levels of suppression index (SI) were compared with the values obtained with normal controls. In contrast, the mean suppression values in the PBL from LN patients in remission and CGN patients with or without nephrotic syndrome, whether the mitogen used was Con A or PHA, were similar to those of the control subjects. Moreover, when individual patients were followed through their clinical illness, LN patients had high levels of SI, particularly in the beginning of acute exacerbations; the SI levels than decreased sharply in the latter phase of relapse and again increased to relatively normal levels with the onset of clinical remission. These in vitro findings suggest that there exists an alteration in Con A-induced SCA in a group of patients with LN.