A non-inflammatory form of immune competence prevails in acute pre-pubescent malnutrition: new evidence based on critical mRNA transcripts in the mouse.

The declining inflammatory immune competence of acute (i.e. wasting) pre-pubescent protein-energy malnutrition has been regarded as reflecting an unregulated immunological disintegration. Recent evidence, however, suggests that malnutrition stimulates a regulated immunological reconfiguration to achieve a non-inflammatory form of competence, perhaps offering protection against autoimmune reactions - the 'Tolerance Model'. Our objective was to determine the influence of acute pre-pubescent malnutrition on the expression of genes critical to tolerogenic regulation. Male and female C57BL/6J mice, initially 19 d old, consumed a complete purified diet either ad libitum (age-matched controls) or in restricted daily quantities (mimicking marasmus), or consumed an isoenergetic low-protein diet ad libitum (mimicking incipient kwashiorkor) for 14 d (six animals per dietary group). Gene expression in the spleen, typically an inflammatory organ, and in the small intestine, a site designed for non-inflammatory defence, was assessed by real-time quantitative RT-PCR, and normalised to ß-actin. In the spleen of the malnourished groups, both IL-10 and transforming growth factor-ß1 mRNA expression increased compared with controls (P < 0.05), whereas mRNA expression of IL-12p40 decreased (P < 0.05). Conversely, malnutrition exerted no influence on the expression of mRNA for these cytokines in the small intestine (P>0.05). Moreover, forkhead box P3 mRNA expression, indicative of cell-based tolerogenic potential, was sustained in both the spleen and intestine of the malnourished groups (P>0.05). Thus, despite limited supplies of energy and substrates, the spleen shifted towards a non-inflammatory character and the intestine was sustained in this mode in advanced pre-pubescent weight loss. These findings provide the first support for the Tolerance Model at the level of mRNA transcript expression.

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.

Influence of nutrition on postvaccinial tuberculin sensitivity.

Response to BCG vaccination was studied in 261 apparently normal preschool children in a community. They were classified into different nutritional groups based on deficit in weight for age. In addition, nine children who had kwashiorkor and were admitted to the hospital were investigated. They were given 0.1 ml of BCG vaccine, and 6 months later, tuberculin sensitivity was assessed using 5 U of PPD. Blood samples were collected from 84 subjects and leukocyte migration inhibition was determined using the same antigen. After BCG vaccination, over 80% of children in the community showed positive tuberculin test, irrespective of the extent of growth retardation. There were no significant differences in the size of induration or the percentage of reactors between the various groups, indicating that the immune response to BCG vaccination is not affected by milder grades of malnutrition. However, the skin test was negative in most of the children who had had kwashiorkor. Leukocyte migration inhibition was similar in all the groups of children including those with kwashiorkor indicating that sensitisation of lymphocytes was not influenced by the nutritional status. In children with kwashiorkor, the leukocyte migration inhibition test was positive though the skin test was negative, suggesting that the former may be a better measure of assessing the response to BCG vaccination.

Complement activity in children with protein-calorie malnutrition.

Using the hemolytic complement (CH50) assay, we evaluated the complement system of 28 children with severe protein calorie malnutrition (PCM) during their hospital admission and recovery. The mean CH50 activity in children with kwashiorkor was significantly less on hospital days 1 and 4 than in 17 healthy control subjects. On day 8 it rose to normal, and by day 50 it was significantly higher than the controls. The mean CH50 titer of 16 well-nourished febrile children was, in contrast to that of untreated PCM, significantly greater than the healthy controls. Of the children with PCM, 11 (40%) evidenced anticomplementary (AC) activity in their serum on either day or 1 or 4, but only two (7%) had detectable serum AC activity during later convalescence. Significantly, the CH50 titer in a PCM serum correlated inversely to the amount of AC activity in that serum (P less than 0.01). These results indicate that, in children with PCM, the complement system is compromised functionally, and that its repair coincides with intake of adequate diet. The presence of AC activity provides a possible mechanism for depressed complement activity in some untreated PCM children.

Effect of renutrition on humoral and cell-mediated immunity in severely malnourished children.

Forty-three Colombian children suffering from either kwashiorkor (21), combined protein-calorie malnutrition (11), or maramus (11) were hospitalized and provided a high protein, high calorie diet for 4 to 5 wk. Improvement in clinical and nutritional status was accompanied by significant increases in levels of serum immunoglobulins G and M and C3 complement and by significant decreases in serum immunoglobulin A concentrations, especially in infants with kwashiorkor. Skin test reactions to purified protein derivative and candidin improved during renutrition. Lymphocyte blastogenesis after stimulation in vitro with phytohemagglutinin and pokeweed mitogen increased rapidly during hospitalization. After 1 yr posttreatment, cell-mediated immune responses, both in vivo and in vitro, had diminished. These results indicate that some aspects of the immune response are affected to a different degree in kwashiorkor, maramus, and combined malnutrition. Short-term nutritional rehabilitation has a differential effect on the long-term restoration of various aspects of immunity.

Defective local leukocyte mobilization in children with kwashiorkor.

The Rebuck window technique was used to determine the functional integrity of the inflammatory response in nine children with kwashiorkor. The total numbers of leukocytes mobilized into skin abrasions were similar between kwashiorkor and control patients. However, children with kwashiorkor showed significantly delayed and decreased macrophage migration and increased polymorphonuclear leukocyte migration. These defects of leukocyte mobilization were corrected with nutritional repair.

In vitro lymphocyte-differentiating effects of thymulin (Zn-FTS) on lymphocyte subpopulations of severely malnourished children.

This work investigates how thymic dysfunction contributes to the depression of cell-mediated immunity in protein-energy malnutrition (PEM). In Bolivian children hospitalized for severe PEM, the size of the thymus was measured by echography, and the lymphocyte subpopulations were detected by using monoclonal antibodies. These data were compared with those obtained from healthy control subjects. Regardless of the clinical form of PEM, our results show a high degree of T lymphocyte immaturity in severely malnourished children, which correlates with a severe involution of the thymus. Before in vitro incubation with thymulin, this significant increase in the percentage of circulating immature T lymphocytes was concomitant with a decrease in mature T lymphocytes and a slight increase in cytotoxic T subpopulations. After in vitro incubation with thymulin, immature T lymphocytes decreased and mature T lymphocytes increased.

Immunoglobulins and antibody response in children with protein-calorie malnutrition.

The immunoglobulin levels (IgG, IgA, IgM, IgD, and IgE) were studied in 28 Northern Thai children with protein-calorie malnutrition (PCM). Of these 14 had marasmus, 7 had marasmus-kwashiorkor, and 7 had kwashiorkor. The immunoglobulin levels were measured on admission and serially during 12 weeks of treatment leading to recovery. All immunoglobulin fractions either equalled or exceeded levels seen in well-nourished urban and rural Thai children, with or without infection. There was no difference in levels of IgG, IgM, IgA, or IgD in children with marasmus when compared with those who had marasmus-kwashiokor or kwashiorkor. IgA levels were higher in malnourished than control children and returned to normal with treatment. Eighty percent of the children with PCM had detectable IgD levels while 64% had detectable IgE levels as compared to none in the control groups. Ten additional children admitted with PCM and 10 who had recovered from PCM were immunized with intradermal typhoid antigen. Within 8 days a significant increase in typhoid H antibody appeared in the recovered group, while the malnourished group demonstrated no significant increase in H antibody titer.

Serum and small intestinal immunoglobulin levels in undernourished children.

Intestinal immunoglobulin levels were quantitated in undernourished Indonesian children with enteric infections and normally nourished Indonesians with and without enteric infections. These were compared to the same parameters in Australian Aboriginal children (also suffering undernutrition) and normal Caucasian children. Children with enteric infections displayed equally elevated levels of intestinal immunoglobulin irrespective of their nutritional status. Intestinal infections appeared to elevate IgG levels more than secretory IgA levels in the age group examined. However, it appeared likely that some of the EgG was serum-derived whereas the IgA appeared to be locally produced. There was no apparent deficiency in the capacity of undernourished children to manufacture and secrete immunoglobulin in the gut.

Nitro blue tetrazolium test in children with kwashiorkor with a comment on the use of latex particles in the test.

The nitro blue tetrazolium test was applied on neutrophils from children with kwashiorkor and from control children. The percentage of formazan cells formed in the kwashiorkor patients was significantly less than in the control group in spite of the presence of associated infections in the former. A direct correlation exists between the percentage of formazan cell formation and total serum proteins, albumin, and haemoglobin. These findings may reflect a decreased bactericidal activity of neutrophils in kwashiorkor. The use of latex particles is an unnecessary technical refinement of the test.

Effect of levamisole on E rosette inhibition by serum of malnourished children.

E rosette forming lymphocyte levels were measured in 5 normal children (in the presence or absence of levamisole) after in vitro gamma globulin (AGG) or sera containing E rosette inhibitory substance obtained from kwashiorkor children. The experiments were repeated using lymphocytes from 5 kwashiorkor children who showed detectable levels of serum E rosette inhibitory substance. There was a diminution in the E rosette formation of normal lymphocytes treated with AGG or with serum of kwashiorkor children having E rosette inhibitory substance. Addition of levamisole in vitro significantly increased the levels of E rosettes. Similarly low levels of E rosettes were demonstrated when lymphocytes of kwashiorkor children were incubated with autologous sera. Treatment with levamisole in vitro also improved the levels of E rosettes.

Leucocyte migration inhibition factor (L-MIF) in malnourished Nigerian children.

Leucocyte Migration Inhibition Factor (L-MIF) was measured in 41 children with marasmus, 19 with kwashiorkor, 5 with marasmic-kwashiorkor and 35 well-fed healthy children serving as controls. For L-MIF assay, two different antigens (live attenuated measles virus vaccine and diptheria pertussis tetanus (DPT) vaccine were used. Percentage migration indices obtained with the two antigens were significantly higher in the malnourished than in the well-fed healthy sex and age-matched controls (P < 0.01). The total serum protein and albumin concentrations were significantly reduced in the malnourished children compared with the controls (P < 0.01). Mean total leucocyte numbers were not significantly different in marasmic and marasmic-kwashiorkor children compared with the controls (P > 0.21).

[Protein-calorie deficiency and the immune processes]. / Belkovo-kaloriinaia nedostatochnost' i immunnye protsessy.

The paper deals with issues that concern the influence of alimentary factors, of protein-caloric deficiency in particular, on the function of the immune system. Subject to a consecutive study was the pathogenesis of disorders in endocytosis of antigens, in humoral and cellular immunity and in reactions of hypersensitivity with proteinic deficiency. An inference is drawn to the effect that immunogenesis and a number of immune reactions are extrmely sensitive to alimentary effects and, above all, to the proteinic deficiency. Mention is also made of the fact that under certain conditions alimentary factors can direct favourably the course of a given immune process.

Constitutive, but not challenge-induced, interleukin-10 production is robust in acute pre-pubescent protein and energy deficits: new support for the tolerance hypothesis of malnutrition-associated immune depression based on cytokine production in vivo.

The tolerance model of acute (i.e., wasting) pre-pubescent protein and energy deficits proposes that the immune depression characteristic of these pathologies reflects an intact anti-inflammatory form of immune competence that reduces the risk of autoimmune reactions to catabolically released self antigens. A cornerstone of this proposition is the finding that constitutive (first-tier) interleukin(IL)-10 production is sustained even into the advanced stages of acute malnutrition. The IL-10 response to inflammatory challenge constitutes a second tier of anti-inflammatory regulation and was the focus of this investigation. Weanling mice consumed a complete diet ad libitum, a low-protein diet ad libitum (mimicking incipient kwashiorkor), or the complete diet in restricted daily quantities (mimicking marasmus), and their second-tier IL-10 production was determined both in vitro and in vivo using lipopolysaccharide (LPS) and anti-CD3 as stimulants of innate and adaptive defences, respectively. Both early (3 days) and advanced (14 days) stages of wasting pathology were examined and three main outcomes emerged. First, classic in vitro systems are unreliable for discerning cytokine production in vivo. Secondly, in diverse forms of acute malnutrition declining challenge-induced IL-10 production may provide an early sign that anti-inflammatory control over immune competence is failing. Thirdly, and most fundamentally, the investigation provides new support for the tolerance model of malnutrition-associated inflammatory immune depression.