Body size and immune responses

Nutrition Research, Vol. 16, Nos. 11112, pp. 1813-1819,1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0271-5317/96$15.00+.00 ELSEVIER

PIISO271-5317(%)00204-7

BODY SIZE AND IMMUNE RESPONSES Ranjit Kumar Chandra’ and Paola Sarchielliz ‘Department of P ediatrics, Memorial University of Newfoundland, Janeway Child Health Centre, St. John’s, Newfoundland, Canada, and *Universita degli Studi, Perugia, Italy.

ABSTRACT Nutritional deficiencies are associated with altered immune responses and increased susceptibility to infection. The changes are most marked in severe deficits of nutrient intake and some nutrients are more critical than others in influencing immunity. Similarly, there is a correlation between body size and immunocompetence. Both protein-energy malnutrition and obesity are associated with changes in selected parameters of immunity. Very little is known about changes in immune responses in stunting. These effects of nutritional status and of body size and composition may be mediated through changes in hormones, cytokines and/or cell number and filIlCtiOIL Copyright Q 1996 Elsevier Science IIIC.

KEY WORDS: Immune responses, cell-mediated immunity, cytokines, hormones, stunting, nutritional status, body size, body composition. INTRODUCTION Rapidly proliferating tissues are very sensitive to changes in nutrient availability and hormonal status. For this reason, it may be expected that subtle changes in the immune system with its rapid turnover of cells and enormous protein synthesis may be observed in mild chronic undernutrition that results in stunting. There is a paucity of

Correspondence and reprint requests to: Prof. R.K. Chandra, MD, Janeway Child Health Centre, St. John’s, Newfoundland AlA lR8, Canada.

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R.K. CHANDRA and F?SARCHIELLI

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data in this field. In this selected review, we shall deal with the immunologic mechanisms of host defense, the progressive impact of reduced nutrient intake, the most sensitive parameters of immunocompetence that are affected by nutritional deficiencies, and the effects of stunting on a few immune responses.

THE IMMUNE SYSTEM Protection from microorganisms and infectious diseases depends upon a variety of interacting mechanisms, both innate and adaptive (Fig. 1). The antigen-specific immunity depends upon antibodies of five different isotypes - IgG, IgA, IgM, IgD, T IgE - and on cell-mediated immunity that relies mainly on thymus-processed lymphocytes. The two tiers of specific immunity have many interactions between them, both enhancing and inhibiting each other. An example of the importance of interaction between T and B lymphocytes is the outcome measure of antibody production. Antigenpresenting cells (e.g. macrophages) facilitate the introduction of antigen both to T and

: MlCROORGANlSi4S

HOST

PARASITES

MALIGNANT

C\ELLS

RESISTANCE

FIG. 1. Host defense mechanisms. These include both nonspecific and antigen-specific processes. [Copyright ARTS Biomedical Publishers 8z Distributors, reproduced with permission].

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B cells. CD4+ T lymphocytes enhance the ability of B lymphocytes to proliferate and change to antibody-producing plasma cells. Similarly, in the primary common varied immunodeficiency, a number of pathogenetic mechanisms may underlie the final failure to produce adequate amounts of functionally adequate antibody. These include paucity of B cells, reduced synthesis or secretion of IgG, reduced number and/or function of CD4+ helper T cells, increased number and/or function of suppressor cells, inactivation of IgG by autoantibody, etc. This topic has been reviewed extensively in various monographs (l-4).

NUTRITIONAL DEFICIENCIES AND IMMUNE RESPONSES With progressive reduction in total energy consumption or individual nutrient intake, there is a depletion of body stores followed soon by impaired immunologic responses that lead inevitably to an increased susceptibility to infection. Some infections may be serious enough to jeopardize survival (Fig. 2). 5.................. ................. .................. .................. .................. ..................

:~~;~~+:.:;+:.~. Depl e ted stores ................... .................. ................... .................. ................... .................. ...................................... .~,~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~,~,::::::::::: ..................................... ...................................... ..................................... ...................................... Immunological changes ........................................................................... ........................................................................... ..................................... ..................................... .

............................................................................................ ................................................................................................................ .::::::‘ .‘:.:::::~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~ :“ ....................................................... ““” .‘............................................... ........................................................ Subclinical infections ........................................................ ........................................................ ....................................................... ........................................................

....................................................... ........................................................ ........................................................................ ............................................................................ .......................................................................... .......................................................................... ................ .................................................................................................................... ................. ................................................................. .................................................................................... Infections ..................................................................................................................................................... .......................................................................... ........................................................................... .......................................................................... ........................................................................... ..........................................................................

.............................................................................................. ............................................................................................. ............................................................................................. .~.~.~.~.~.~.~.~.~.::‘ .‘.::::‘.~.~.~.~.~.~.~.~.~.::~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~.~. ............................................................................................. . Death ............................................................................................. ............................................................................................. ..............................................................................................

.......................................................................................................................................................................... ............................................................................................. ..............................................................................................

)-

Decreasing

Nutrient

Intake

-L

FIG. 2. Consequences of a progressive reduction in nutrient intake.

There are many reasons for the increased incidence and severity of infection in underprivileged malnourished individuals and populations. These include overcrowding, poor sanitation, inadequate personal hygiene, poor nutrition and health education. In

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R.K. CHANDRA

and P. SARCHIELLI

addition, impaired immunocompetence may play a significant role. In nutritional deficiencies, a variety of host defense mechanisms are breached (Fig. 3).

FIG. 3. In malnutrition, many of the host defenses are breached, allowing microbes to invade and produce clinical infection that is more severe and prolonged. [Copyright ARTS Biomedical Publishers & Distributors, reproduced with permission].

Changes in the immune system in protein-energy malnutrition and in individual nutrient deficiencies include impaired delayed cutaneous hypersensitivity, decreased number of T lymphocytes specially helper CD4+ cells, reduced lymphocyte proliferation response to mitogens and antigens, decreased production of cytokines particularly interferon-gamma and interleukin-2, reduced natural killer cell activity, impaired ability of phagocyte to kill ingested bacteria and fungi, lower levels of complement components C3 and Factor B, and reduced secretory IgA antibody responses on mucosal locations. These aspects of interactions between nutrition and immunity have been reviewed elsewhere (5-10).

IMMUNOLOGICAL

INDICATORS

OF NUTRITIONAL

STATUS

We have previously reviewed our thesis that immunological tests can serve as sensitive and functional indices of nutritional status (11,12). The parameters that have

STUNTING AND IMMUNITY

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proven useful in this regard include number of T lymphocytes particularly CD4 cells and CD4 +/CD8 + ratio, quantitative assessment of delayed cutaneous hypersensitivity (Fig. 4), levels of complement C3 and Factor B, production of interleukin-2, leukocyte terminal deoxynucleotidyl transferase activity, and serum thymulin activity. The methodology, utility and drawbacks of these tests have been described (13). . 20

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Serum

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5-

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AlbumIn

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( g/dl)

FIG. 4. Correlation between delayed cutaneous hypersensitivity expressed as a cumulative induration score and serum albumin concentration.

IMMUNOLOGIC

RESPONSES IN STUNTED

CHILDREN

There are no previous data on the immunocompetence of stunted children. Our first study on this topic involved 90 infants with various types of chronic, acute on chronic, and acute malnutrition (14). Most of the children belonged to the marasmus category. We have recently collected limited data on young children who would fit the current definition of stunting and this information is shown in Table 1. Clearly, there are small differences in selected immunologic responses of stunted and normal children. Stunted children have lower cumulative scores of delayed cutaneous hypersensitivity. This may be a reflection of impaired cell-mediated immunity and T lymphocyte dysfunction or it may be due to poor mobilization of mononuclear cells or both these factors. It would be useful to measure interleukin-1 production and this is being done currently. There was a slight reduction in bacterial killing by neutrophils. This may be a reflection of inadequate oxidative burst and other microbial killing mechanisms in microphages. In addition, the serum thymulin activity was lower in stunted children. This may be a reflection of relative zinc deficiency.

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R.K. CHANDRA and P. SARCHIELLI

Table 1. Selected immunologic responses in two groups of age-matched children.

Immunologic test

stunted

Healthy

Delayed cutaneous hypersensitivity (mm)

10.2 [2.4]

16.7 [1.8]*

CD3 + cells

62.4 [4.5]

68.1 [3.1]

CD4+ cells

44.3 [4.1]

45.7 [5.7]

CD4 + /CD8 + ratio

2.2 [0.3]

2.4 [0.4]

Bacterial killing (%)

78.3 [5.6]

94.1 [2.1]*

Natural killer cell activity (%)

43.2 [5.6]

49.7 [4.3]

48 [g-128]

% [32-256]*

Serum thymulin activity

(median reciprocal titre and range)

Number of study subjects 14 in each group. * P c 0.05 Other values do not differ significantly between the two study groups.

CONCLUDING REMARKS Limited data suggest that there may be subtle differences in selected immtmologic responses of stunted children when compared with age-matched controls. Differences in hormonal levels, including growth hormone, free cortisol and thyroxine, all of which have important immunomodulatory effects on the immune system, may be one explanation for these changes. In addition, the role of cytokines and the relative functional deficiency of nutrients such as zinc needs to be looked at. Such studies are now planned and in progress.

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REFERENCES 1. Chat&a RK. Primary and secondary immunodeficiency disorders. Edinburgh, Churchill Livingstone, 1983. 2. Abbas AK, Lichtman AH, Pober JS. Cellular and molecular immunology. Philadelphia, Saunders, 1991. 3. Bellanti JA. Immunology. Philadelphia, Saunders, 1994. 4. Roitt I, Brostoff J, Male D. Immunology. London, Mosby, 19%. 5. Chandra RK, Newbeme PM. Nutrition, immunity and infection;mechanisms of interactions. New York, Plenum, 1977. 6. Suskind RM. Malnutrition and the immune response. New York, Raven, 1978. 7. Hambreaus L, Hanson LA, McFarlane H. Food and immunology. Stockholm, Almqvist & W&sell, 1978. 8. Beisel WR. Single nutrients and immunity. Am J Clin Nutr 1982;35:417-468. 9. Gershwin E, Beach R, Hurley L. Nutrition and immunity. New York, Academic Press, 1984. 10. Char&a RK. McCollun award leture. Nutrition and immunity. Lessons from the past and new insights into the future. Am J Clin Nutr 1991;53:1087-1110. 11. Char&a RK. Immunocompetence is a functional index of nutritional status. Brit med Bull 1981;37:89-94. 12. Chandra RK, Sarchielli P. Nutritional status and immune responses. Clinics La Med 1993;13:455-461. 13. Sarchielli P, Chat&a RK. Immunocompetence methodology. In Fidanra F,ed. Nutritional status assessment. London, Chapman and Hall, 1991:425-445. 14. Char&a RK. Immunocompetence in undernutrition. J Pediatr 1972;81: 1194-1200. Accepted

for

publication

July

11,

1996.