The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases. Interestingly, it has been reported that autism subjects often have associations with HLA genes/haplotypes, suggesting an underlying dysregulation of the immune system mediated by HLA genes. Genetic studies have only succeeded in identifying autism-causing genes in a small number of subjects suggesting that the genome has not been adequately interrogated. Close examination of the HLA region in autism has been relatively ignored, largely due to extraordinary genetic complexity. It is our proposition that genetic polymorphisms in the HLA region, especially in the non-antigen-presenting regions, may be important in the etiology of autism in certain subjects.

In adherent and motile neutrophils NAD(P)H concentration, flavoprotein redox potential, and production of reactive oxygen species and nitric oxide, are all periodic and exhibit defined phase relationships to an underlying metabolic oscillation of approximately 20 s. Utilizing fluorescence microscopy, we have shown in real-time, on the single cell level, that the system is sensitive to externally applied periodically pulsed weak magnetic fields matched in frequency to the metabolic oscillation. Depending upon the phase relationship of the magnetic pulses to the metabolic oscillation, the magnetic pulses serve to either increase the amplitude of the NAD(P)H and flavoprotein oscillations, and the rate of production of reactive oxygen species and nitric oxide or, alternatively, collapse the metabolic oscillations and curtail production of reactive oxygen species and nitric oxide. Significantly, we demonstrate that the cells do not directly respond to the magnetic fields, but instead are sensitive to the electric fields which the pulsed magnetic fields induce. These weak electric fields likely tap into an endogenous signaling pathway involving calcium channels in the plasma membrane. We estimate that the threshold which induced electric fields must attain to influence cell metabolism is of the order of 10(-4) V/m.

Although much progress has been made in elucidating the mechanisms underlying the physiological regulation of fever, there is little understanding of the biological utility of fever’s thermal component. Considering the evolutionary co-conservation of fever and innate immunity, we hypothesize that fever’s thermal component might in general augment innate immune function and, in particular, neutrophil activation. Accordingly, we have evaluated the effect of febrile temperatures on neutrophil function at the single-cell level. We find that reactive oxygen intermediates and NO release are greatly enhanced at febrile temperatures for unstimulated as well as LPS-stimulated adherent human neutrophils. Furthermore, our studies suggest that these changes in oxidant release are linked to upstream changes in NADPH dynamics. Inasmuch as reactive oxygen intermediates and NO production are important elements in innate immune responses to bacterial pathogens, we suggest that the febrile rise in core temperature is a broad-based systemic signaling mechanism to enhance innate immunity.

No abstract

Metabolic activity in eukaryotic cells is known to naturally oscillate. We have recently observed a 20-s period NAD(P)H oscillation in neutrophils and other polarized cells. Here we show that when polarized human neutrophils are exposed to interferon-gamma or to ultra-low-frequency electric fields with periods double that of the NAD(P)H oscillation, the amplitude of the NAD(P)H oscillations increases. Furthermore, increases in NAD(P)H amplitude, whether mediated by interferon-gamma or by an oscillating electric field, signals increased production of reactive oxygen metabolites. Hence, amplitude modulation of NAD(P)H oscillations suggests a novel signaling mechanism in polarized cells.