Involvement of the IFN-gamma pathway in a patient with candle syndrome carrying a novel variant of PSMB8 gene

Individual and combined effects of several isomers of retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on interferon-gamma (IFN-gamma) secretion by blood mononuclear leukocytes (MNL) from nulliparous and postparturient Holstein cattle were evaluated in vitro. In the first experiment, effects on incubation period (24 to 72 hours) and time of supplementation (0 to 32 hours) with all-trans, 9-cis, 13-cis-, and 9,13-dicis-RAs (0 to 100 nM) on IFN-gamma secretion by pokeweed mitogen (PWM)-stimulated (0 and 10 mug/ml) MNL from nulliparous cattle were evaluated. In the second experiment, MNL from postparturient cows (bled at 0, 2, 4, and 16 days postpartum) were stimulated with PWM (0 and 10 mug/ml) in the presence of RA isomers (9-cis- or 9,13-dicis-RA; 0 to 100 nM), 1,25-(OH)2D3 (0 to 100 nM), or with combinations of these metabolites. The results show that individual isomers of RA had no effect on IFN-gamma secretion by PWM-stimulated MNL from nulliparous or postparturient cows. Furthermore 1,25-dihydroxyvitamin D3 inhibited IFN-gamma secretion by MNL from nulliparous and postparturient dairy cows; however, the degree of inhibition was greater when 9-cis- and 9,13-dicis-RA were also present in the cultures. Finally mononuclear leukocytes from postparturient dairy cows produced substantially less IFN-gamma than did MNL from nulliparous cattle. It is concluded that retinoic acids individually did not affect the capacity of leukocytes from dairy cattle to secrete IFN-gamma. This result is in marked contrast to studies in monogastric species indicating that RAs inhibit IFN-gamma secretion by peripheral blood T cells. Inhibition of IFN-gamma secretion by 1,25-(OH)2D3 was potentiated by 9-cis- and 9,13-di-cis-retinoics acids, suggesting that an excess of dietary vitamins A and D may compromise further the naturally immunosuppressed postparturient dairy cow. Additional research is necessary to determine if the combined effects of these metabolites on IFN-gamma secretion represent an increased susceptibility of the dairy cow to infectious diseases during the periparturient period. Lower secretion of IFN-gamma by MNL from postpartutient dairy cows, relative to nulliparous cattle, suggests that recently-calved cows are naturally immunosuppressed.

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Effects of Increased Dietary Protein and Energy on Composition and Functional Capacities of Blood Mononuclear Cells from Vaccinated, Neonatal Calves

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.75.5.357 ◽

2005 ◽

Vol 75 (5) ◽

pp. 357-368 ◽

Cited By ~ 8

Author(s):

Foote ◽

Nonnecke† ◽

Waters ◽

Palmer ◽

Beitz ◽

...

Keyword(s):

Weight Gain ◽

B Cell ◽

Dietary Protein ◽

Crude Protein ◽

Interleukin 2 ◽

Milk Replacer ◽

Standard Diet ◽

Gamma Delta ◽

Ifn Gamma ◽

Functional Capacities

Effects of increased protein and energy provided by an intensified milk replacer on the antigen-specific, cell-mediated immune response of the neonatal calf were examined. Calves were fed a standard (0.45 kg/day of a 20% crude protein, 20% fat milk replacer; n = 11) or intensified (1.14 kg/day of a 28% crude protein, 20% fat milk replacer; n = 11) diet from 0 to 6 weeks of age. All calves were vaccinated with Mycobacterium bovis bacillus Calmette-Guerin (BCG) at 1 week of age. The daily weight gain of intensified-diet calves (0.62 kg/day) was greater than the weight gain of standard-diet calves (0.29 kg/day). Liver, kidney, heart, thymus, and subcervical lymph nodes from intensified-diet calves were heavier than the same organs from standard-diet calves. Flow cytometric analysis of peripheral blood mononuclear cell (PBMC) populations indicated that CD4+ cells, gamma delta TCR+ cells, and monocyte percentages, although unaffected by diet during the first 5 weeks of the study, were higher in intensified-diet calves at week 6. The decline in gamma deltad TCR+ cell percentages and increase in B cell percentages with increasing age seen in all calves are characteristic of the maturing immune system of the calf. CD8+ T cell or B cell percentages were not affected by diet. In intensified-diet calves, percentages of CD4+ expressing interleukin-2 receptor increased and percentages of gamma delta TCR+ cells expressing interleukin-2 receptor decreased with time. The same populations in standard-diet calves did not change with time. Percentages of CD4+ and CD8+ T cells, and B cells expressing MHC class II antigen, were unaffected by diet or age. Although mitogen-induced interferon (IFN)-gamma and nitric oxide (NO) secretion increased with age for all calves, PBMC from intensified-diet calves produced less IFN-gamma and more NO than did cells from standard-diet calves at week 6 of the study. Antigen-induced secretion of IFN-gamma and NO also increased with age but was unaffected by diet. Antigen-elicited delayed-type hypersensitivity was unaffected by diet, suggesting increased dietary protein and energy did not alter adaptive immunity in vivo. Overall, these results suggest that feeding calves a commercially available, intensified milk replacer affects minimally the composition and functional capacities of PBMC populations. Additional research is necessary to determine whether these subtle effects influence the calf’s susceptibility to infectious disease.

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