Introduction and Overview

Nutrients are primary factors in the regulation of the human immune response. Both macronutrients and micronutrients derived from the diet affect immune-system function through actions at several levels in the gastrointestinal tract, thymus, spleen, regional lymph nodes and immune cells of the circulating blood (Chandra, 1997; Cunningham-Rundles and Lin, 1998; Wallace et al., 2000; Cunningham-Rundles, 2001). Effects at one level may be opposed or modified at another level. Thus, the development of an experimental approach capable of revealing critical interactions requires study of more than one aspect of immune function (Cunningham-Rundles, 1993; Muga and Grider, 1999; Beisel, 2000). The effect of any single nutrient is dependent upon concentration, interactions with other key nutrients, host genetic expression and internal environmental conditions. In situations of nutrient imbalance, duration of the altered condition and age of the host are also often critical factors (Cunningham-Rundles and Cervia, 1996; Hirve and Ganatra, 1997; Miles et al., 2001).

Nutrients affect specific immune-cell types differently through influencing intrinsic cell function and by influencing cell-cell interactions. Much of the critical action appears to occur in the local microenvironment during the response to antigen. Classically, the immune system has been considered as an operational duality divided into an innate system, mediating immune reactions that do not functionally change with re-exposure to signal, and an adaptive immune system, which is capable of developing the response to antigen encounter and evolving with re-exposure. Adaptive immunity has been further characterized according to cell type, as the response of bone-marrow-derived B-cells of the humoral immune system and thymus-derived T-cells of the cellular immune system. This rather static picture of compartmentalized function is changing. Now, it is increasingly clear that significant T-

© CAB International 2002. Nutrition and Immune Function (eds P.C. Calder, C.J. Field and H.S. Gill)

cell differentiation does occur independently of the thymus - for example, in the gastrointestinal tract. Current studies also show that the innate immune system, mediated by such cells as natural killer (NK) and NK T-cells, monocytes and dendritic cells, influences the nature of cytokine production by the adaptive immune system. This occurs through secretion of cytokines by innate immune cells into the microenvironment (Doherty et al., 1999; Garcia et al., 1999; see also Devereux, Chapter 1, this volume). The effect of the microenvironment is to drive the immune response towards either a T-helper type 1 (Th1) or a T-helper type 2 (Th2) response (see Devereux, Chapter 1, this volume). Micronutrients, such as trace elements and vitamins, are present in the local environment and have important regulatory effects on adaptive immune-cell function. For example, the trace element zinc supports a Th1 response, whereas vitamin A appears to produce a Th2 response (Frankenburg et al., 1998; Shankar and Prasad, 1998). Thus the new immunology provides a more fluid representation of a potentially evolving process that presents as a defined pattern according to an environmental dynamic rather than a static programme that is derived from fixed cellular characteristics. The basic elements are shown in Fig. 2.1.

Classical analysis

Current analysis

Classical analysis

Current analysis

  • Innate immune system
  • Microenvironment ■ Antigen-presenting
  • Phagocytes
  • NK cells cells
  • NK and NK T-cells
  • Cytokine milieu
  • Adaptive immune system
  • Humoral: B-cells
  • Cellular: T-cells

□ CD8

  • Antigen processing
  • MHC class I
  • MHC class II
  • Super antigen
  • CD1-restricted
  • Response pathways

Fig. 2.1. Microenvironment of immune response. APC, antigen-presenting cell; IFN-7, interferon-7; IL, interleukin; MHC, major histocompatibility complex.

Age of the host or developmental stage is often a critical variable. Antigen-specific humoral and cellular immunity are central to the adaptive immune response generated in the adult host. In contrast, neonates and infants rely primarily on innate immunity, specifically complement, maternal antibody, circulating mediators of the inflammatory response and phagocytes (see Brandtzaeg, Chapter 14, this volume). However, many of the components of innate immunity are not as functional in young children as in adults (Insoft et al., 1996; see also Chapter 14). Encounters with potential pathogens, such as parasitic infections or viruses, may easily compromise these resources. Study of this permits a glimpse of how the naive immune system copes with the sudden influx of signals, new antigens and potential pathogens. When malnutrition is present, the overall development and expression of the immune response are significantly impaired (Cunningham-Rundles et al., 2000, 2002; see Chandra, Chapter 3, this volume). Similarly, the ageing process affects nutrient needs and the immune response in an interactive fashion. The effect of ageing on the response to immunization and the enhancing effects of micronutrients are well known (Lesourd, 1997; Pallast et al., 1999; see Lesourd et al., Chapter 17, this volume). In addition, there are fundamental age-related changes, which may reflect inflammatory processes (see Chapter 17), such as the report that plasma levels of certain adhesion molecules increase with age and appear to influence the impact of dietary fish oil supplementation (Miles et al., 2001).

Assessment of how nutrients may interact in human immune function is a complex undertaking, more difficult than the assay of the response to a specific antigen of interest - for example, the serological antibody response to a virus. In the latter case, it is usually possible to know what level of response correlates with protection. Because of the great specificity and sensitivity of this information, some of the best data regarding nutrient interaction with the human immune system have been based on the use of response to specific pathogens as the point of reference. However, extrapolation from specific settings may be hazardous. It is seldom clear that immune deficiencies in vitro will predict immune deficiency in vivo. Therefore, investigators often seek to strengthen inferences by inclusion of in vivo tests, such as delayed-type hypersensitivity measured by skin testing, and by assessment of the humoral immune response through assay of specific antibodies arising in response to primary or secondary (booster) immunization. Consistency of an altered immune response in the absence of acute clinical presentation continues to serve as the benchmark indicator of a putative intrinsic immune defect. By analogy, repeated studies in the absence of the acute clinical process are crucial for the study of immune changes secondary to chronic malnutrition.

General assessment of the anatomy of the immune system in humans includes measurement of serum immunoglobulins and complement and the evaluation of lymphocyte subsets by immunophenotyping. Analytical studies require selection among a wide range of tests that measure immune function in vitro or ex vivo as a reflection of the immune response in vivo (Kramer and Burri, 1997; Jaye et al., 1998; Cunningham-Rundles, 1999; Bergquist et al., 2000). A basic panel of tests is also required to reveal how the overall balance of the immune system has been affected. Immune studies are often based on limited studies of immune-cell subsets, serum or plasma concentrations of cytokines or the functional response of mononuclear cells cultured in highly standardized systems, using a chosen stimulus and often a single end-point. Newer methods have made it possible to assess differentiation in antigen expression on peripheral-blood mononuclear cells in response to activation, to study early events in the activation pathway and to analyse gene activation.

The development of cytokine biology has provided a critical means of clarifying the fundamental impact of nutrients on immune response. In general, nutrients appear to affect the immune system most profoundly through regulatory mechanisms affecting the expression and production of cytokines (e.g. Savendahl and Underwood, 1997; Rink and Kirchner, 2000). Since the type of cytokine pattern produced is crucial for the response to infectious pathogens, serious nutrient imbalance will ultimately compromise the development of the future immune response. However, while malnutrition promotes susceptibility to pathogens, even subclinical infections directly affect nutrient intake and metabolism. Severe, acute infection will have a very strong impact. The fact that cytokine production during the acute-phase response to generalized sepsis can lead to loss of lean tissue and body fat is well known (Lin et al., 1998). Interestingly, this cascade of events can be altered by nutritional intervention (Jeevanandam et al., 1999). Immune deficiency and susceptibility to infection are often directly linked with malnutrition, which was the leading cause of acquired immune deficiency before the appearance of the human immunodeficiency virus (HIV). Malnutrition is also a major factor contributing to the progression of HIV infection, especially in less developed countries. Since malnutrition and HIV affect the host in similar ways, the combination is particularly devastating. Many of the infections observed in human protein-energy malnutrition (PEM), such as tuberculosis, herpes, Pneumocystis carinii pneumonia and measles, are caused by intracellular pathogens, indicating that the cellular immune system is particularly affected (Keusch, 1993; see Chandra, Chapter 3, this volume).

While the effects of infection and malnutrition on the immune response are interactive, the effects of each upon immune response are also independent. A recent examination by Mishra et al. (1998) of graded PEM in children in relationship to tuberculosis infection and response to a skin-test anergy panel, including purified protein derivative of M. tuberculosis (PPD), has shown that impaired cellular immunity was observable in all grades of malnutrition, except for response to PPD in grade I, and that infection did not affect this.

Differentiation of lymphocyte subpopulations is also directly affected by malnutrition. Studies show that T-cells from children with severe PEM are immature, compared with those from well-nourished children, and that the degree of immaturity is directly associated with thymic involution, as measured by echo radiography (Parent et al., 1994). While nutritional repletion affected anthropometric measures within 1 month, regrowth of the thymus took longer (Chevalier et al., 1996, 1998). The long-term consequences of slow thymic regrowth are unknown. These studies underscore the importance of longitudinal studies.

Response to certain pathogens may actually be enhanced in some states of malnutrition. Genton et al. (1998) assessed the incidence of malaria in children in Papua New Guinea, and found that increased height-for-weight at baseline (an indicator of a better nutritional state) predicted susceptibility to malaria during the year of study and that the lymphocyte response to malarial antigens was lower among the less wasted children. Furthermore, cytokine production towards malarial antigens was greater among malnourished children, suggesting that a favourable cytokine regulatory shift might be the basis of improved response among stunted, but not wasted, children. Stunting has often been considered as an adaptive and partially protective host response to prolonged nutrient deprivation. Rikimaru et al. (1998) evaluated lymphocyte subpopulations and immunoglobulins among healthy children and children with kwashiorkor, marasmus and marasmic kwashiorkor in Ghana. Interestingly, immunoglobulin A (IgA) and C4 were higher, whereas C3 and relative B-cell percentage were lower, in the severely malnourished groups. These studies demonstrate the advantages of using linked measurements to develop a full immunological profile.

In summary, the study of nutrient immune interaction requires consideration of the setting and a design that includes evaluation of possible complementary effects at more than one level. Longitudinal studies are often useful and permit assessment of the evolution of the immune response and characterization of downstream effects, which may modulate outcome.

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