Immune dysfunction and malnutrition

Malnutrition in the neonatal period and early childhood can lead to severe immune deficiency and high mortality. Effects on the immune system are broad, involving all limbs of the immune system, with impaired T cell responses secondary to effects on thymic architecture and function being the most common. The link between malnutrition and infection is readily observable. For children living a rural environment in a developed country, one study reported that bacterial infections were discovered in one third of all patients hospitalized for malnutrition [28]. Malnutrition was also frequently found among adults hospitalized for nosocomial infections in another study [29]. Host response to infection is also altered in malnutrition. Thus, children who were well nourished were found to show a relative increase in B lymphocytes in response to bacterial infection, while B cell response was significantly reduced in malnourished children [30].

Innate immune defects

The innate immune system provides the first line of defense against infection. Defense mechanisms include barrier functions, which require both anatomic components such as specialized epithelium, products such as mucus, and soluble mediators such as cytokines, interferons (IFNs), lyso-zymes, and defensins. Loss of barrier function due to malnutrition promotes infection. Studies in a mouse model of visceral leishmaniasis have shown that malnutrition promoted visceralization through loss of lymph node barrier function after Leishmania donovani infection. This was caused by excessive production of prostaglandin E2, and decreased levels of IL-10 and nitric oxide (NO) [31]. The effect of diet on mucosal integrity is a key measure of nutritional rehabilitation in infants [32]. Protein deficiency predisposes both to skin and mucosal atrophy and compromises barrier function.

Chemotaxis, phagocytosis, and microbial killing mechanisms are potentially impaired in malnutrition through reduced production of key mediators including complement C3, leukotrienes, cathelicidin antimicrobial peptide and leptin [33-36]. Children who are malnourished mount a partial acute phase response to infection and this defect is more marked in children with the edematous form [37]. The activities of innate immune cells such a neutrophils, monocytes, macrophages, and dendritic and NK cells are affected by altered nutrient levels [38-43]. These effects can be particularly critical in the perinatal period of immune development [44, 45].

The development of immune response in the neonate occurs in the context of initial microbial antigen exposure when neonates are also vulnerable to bacterial infection due to immature innate and adaptive immune response. Neonates have deficiencies of innate cellular immunity including decreased production of IFNs, IL-12/IL-23, and IL-18, proinflammatory cytokines, and impaired monocyte response to IFN-y and to lipopolysaccharide (LPS) [46]. Response to bacterial antigens involves microbial antigen binding to the Toll-like receptors (TLRs), which recognize conserved molecular products derived from various classes of pathogens, such as gram-positive (TLR-2) and gram-negative (TLR-4) bacteria, leading to production of inflammatory cytokines and chemokines. Nutrient regulators of this process include 1,25-dihydroxyvitamin D3, which is an immune system modulator that induces expression of the TLR4 coreceptor CD14. 1,25-Dihydroxyvitamin D3 is a direct regulator of antimicrobial innate immune responses and causes secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa, a well-known major pathogen in CF [35].

As shown by studies in experimental gnotobiotic models, protective colonization of mucosal surfaces by commensals has an important stimulatory effect on postnatal development of immune responses, and metabolic processes central to nutrition, and the development of mucosal (oral) tolerance. Nutrient status affects the development of this system [47, 48]. The role of commensals in maturation of the TLR system is currently being studied [49].

Thymic atrophy caused by PCM is associated with hormonal imbalance, loss of leptin, and increase in serum glucocorticoid level. Leptin levels normally increase acutely during infection and inflammation [24], but this does not occur in PCM. The reduction of serum leptin levels and insulinlike growth factor-1 (IGF-1) in marasmus and kwashiorkor [50] may compromise response to infection. Loss of immune function in malnourished children correlates with low leptin levels, and refeeding leads to increase in leptin levels and immunological recovery [51].

Adaptive immune defects

Defects in T cell immunity are characteristic of malnutrition and lead to increased susceptibility to intracellular pathogens, reactivation of viral infections, and development of opportunistic infections [1, 52]. Malnutrition activates the metabolic switch that controls T cell activation and apoptosis [53]. The effects of undernutrition in infancy may extend beyond this period due to effects on programming that are now becoming appreciated. A study of antibody response to typhoid vaccine among adolescents has shown that the likelihood of mounting an adequate response was diminished among the group who were small for gestational age compared to those who were appropriate for gestational age at birth [54]. Age-related effects of malnu trition on immune response have also been found in adults. A recent study in healthy volunteers consisting of younger and older adults showed that short-term fasting had a significant effect on total, helper, and cytotoxic T and B lymphocytes and that this response was significantly and negatively affected by older age [55].

T cell deficiencies in malnutrition are directly attributable to profound lymph node germinal center depletion and thymic atrophy, which can appear similar to primary immune deficiency [56]. Lymphopenia is common. The T cell functional defects resemble those of congenital thymic aplasia as in Di George syndrome [50, 56]. The selective effect of malnutrition on the thymus gland is due to apoptosis-induced thymocyte depletion, affecting the immature CD4+ and CD8+ cells, as well as a decrease in cellular proliferation. Hormonal imbalance, involving decrease of leptin and consequent increase in serum glucocorticoid hormone levels can be reversed with nutritional rehabilitation [57]. Morphological changes in thymic epithelial cells are associated with decreased thymic hormone production. Lymphopenia is commonly observed in malnutrition with an incidence of about 25% in children with fatal malnutrition. This effect on hematopoiesis is now understood as the result of a critical regulatory effect on both B and T cell development that is caused by accompanying zinc deficiency [58]. The absolute number of T cells is directly decreased by zinc deficiency. CD4+ T cells are reduced more than CD8+, resulting in a reversed CD4:CD8 ratio. Other effects of zinc deficiency include defective T cell activation, reduced maturation to a memory phenotype, and impaired cytokine synthesis. T cell deficiencies in zinc deficiency may approach the severity seen in children with combined immunodeficiency (SCID) or advanced HIV infection.

The humoral immune system is generally relatively preserved in malnutrition. Serum levels of IgA1, IgA2 and C4 tend to be higher than in normal children, while serum level of C3 and the proportion of B cells are significantly lower [43]. IgE levels are lower even among asthmatic children [59]. Response to immunization tends to be normal and therefore vaccines remain effective [60].

Malnourished children at risk for tuberculosis (TB) often do not respond to Bacille Calmette-Guerin (BCG) immunization, shown by negative tuberculin skin test, and have an increased risk for developing disseminated systemic TB compared to well-nourished children who usually have mild localized disease and rarely present with hematogenous spread [61]. Current studies show a low protective effect of BCG vaccination against all forms of TB among vaccinated children as defined by visible scar and somewhat better efficacy against extra-pulmonary TB [62]. The role of nutritional status in children at the time of vaccination has not been fully evaluated. Since disseminated BCG infection in immune deficiency remains a serious concern, studies to examine the interaction with malnutrition would be informative [63].

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