Parenteral Nutrition (PN) Impairs Gut-associated Lymphoid Tissue (GALT) and Mucosal Immunity by Reducing Lymphotoxin β Receptor (LTβR) Expression
Woodae Kang, MD, PhD*, Enrique F. Gomez, PhD*, Jinggang Lan, PhD*, Yoshifumi Sano, MD*, Chikara Ueno, MD*, Kenneth A. Kudsk, MD
The University of Wisconsin–Madison, Madison, WI, University of Wisconsin, Madison, WI
OBJECTIVE: Lack of enteral stimulation with PN impairs mucosal immunity and IgA levels through depression of GALT cytokines (IL-4 and IL-10) and adhesion molecules (e.g. MAdCAM-1). We have shown that each is critical to intact mucosal immunity through effects on lymphocyte homing, IgA production and resistance to anti-bacterial and anti-viral immunity. IgA is the principal specific immunologic mucosal defense. LTβR stimulation controls production of IL-4, MAdCAM-1 and other key components of GALT, all of which increase IgA levels. We studied the effects of PN on LTβR expression.
METHODS: Experiment 1: LTβR expression in murine intestinal and Peyer’s patches (PP) were analyzed by Western blot analysis after 5 days of chow, a complex enteral diet (CED), or PN. Diets were isocaloric and isonitrogenous except for chow. Experiment 2: Mice received chow, PN + 10 μg (2 x 5 μg i.v./day) of anti-LTβR agonistic antibody, or PN + isotype control antibody. PP lymphocytes and intestinal IgA levels were measured after 2 days.
RESULTS: Lack of enteral stimulation with PN significantly decreased LTβR expression in intestine and PP compared to chow and CED. LTβR stimulation significantly increased PP lymphocyte counts and intestinal IgA in PN fed mice.
|Experiment 1. Effects of PN on LTβR expression.|
|Chow (n=11)||167.6 ± 14.9*||146.7 ± 38.3*|
|CED (n=10)||167.9 ± 23.3*||136.9 ± 26.8*|
|PN (n=12)||111.3 ± 42.8||104.9 ± 47.1|
|Experiment 2. Effects of anti-LTβR agonist.|
|Group||Cells (X106)||IgA levels (μg)|
|Chow (n=11)||29.6 ± 8.1†||205.4 ± 57.0†|
|PN + isotype control antibody (n=11)||18.4 ± 5.6||121.0 ± 55.6|
|PN + anti-LTβR agonistic antibody (n=13)||24.5 ± 7.3†||177.0 ± 78.9†|
Values are means ± SD. *p<0.05 vs. PN, †p<0.05 vs. PN + isotype control antibody by Fisher’s protected least significant difference test.
CONCLUSIONS: LTβR expression is critical for GALT control mechanisms and intact mucosal immunity. PN reduces LTβR expression, PP lymphocytes and intestinal IgA production. Exogenous LTβR stimulation reverses PN-induced depression of gut mucosal immunity.
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