This review describes mechanisms of immune-to-brain signaling that may contribute to disease-related changes in mood, affect and behavior in chronic inflammatory rheumatic diseases. The central ...nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. These immune cells relay information back to autonomic, limbic and cortical areas of the CNS to affect neural activity and consequently modify behavior, hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events relating to infection and injury. Equally important, homeostatic mechanisms are needed at all levels to turn off the immune response when the pathogen and injurious condition are eliminated and the repair process is completed. In individuals with chronic inflammatory diseases, such as rheumatoid arthritis (RA), there is a failure of the homeostatic regulation leading to long-term immune activation that has serious health consequences. Rheumatic disorders constitute a challenge to major psychological adaptation resources leading to higher rates of psychological disorders compared with the general population. Thus the relationship between disease pathology and psychological well being is complex.
Combined treatment with terbutaline, a beta-AR agonist, and phentolamine, a alpha-AR antagonist, (SH1293) after disease onset reduced disease severity in rats with adjuvant-induced arthritis (AA) ...(Lubahn et al., 2004). Here, we investigated the effects of SH1293 on sympathetic innervation and bone integrity in the ankle joint. On day (D) 0, male Lewis rats were immunized with complete Freund’s adjuvant to induce AA. From D12 (disease onset) through D21 or D28, rats were intraperitoneally treated twice-daily with vehicle or SH1293 (1200 mg terbutaline and 125 mg phentolamine/day in 250 ml). Ankle joints were evaluated for lymphocyte infiltration, bone area and volume, osteoclast number, cartilage and pannus area using routine histology, and sympathetic innervation using immunohistochemistry for tyrosine hydroxylase. SH1293 preserved cartilage area, and bone volume (D21 and D28) and reduced pannus formation and synovial lymphocyte infiltration compared with controls. Bone area and osteoclast counts revealed high and low responders to SH1293. High-responders had increased bone area and lower osteoclast numbers. AA reduced sympathetic nerve density, an effect transiently attenuated by SH1293. No significant correlations were observed between variables for joint destruction and between nerve density and these variables with SH1293 treatment. Collectively, these findings are consistent with reports in RA patients, and support sympathetic regulation in disease-mediated joint destruction that can be targeted with adrenergic receptor drugs for therapeutic benefits in autoimmune arthritis.
Optimal host defense against pathogens requires cross-talk between the nervous and immune systems. This paper reviews sympathetic-immune interaction, one major communication pathway, and its ...importance for health and disease. Sympathetic innervation of primary and secondary immune organs is described, as well as evidence for neurotransmission with cells of the immune system as targets. Most research thus far has focused on neural-immune modulation in secondary lymphoid organs, has revealed complex sympathetic modulation resulting in both potentiation and inhibition of immune functions. SNS–immune interaction may enhance immune readiness during disease- or injury-induced ‘fight’ responses. Research also indicate that dysregulation of the SNS can significantly affect the progression of immune-mediated diseases. However, a better understanding of neural-immune interactions is needed to develop strategies for treatment of immune-mediated diseases that are designed to return homeostasis and restore normal functioning neural-immune networks.
Abstract Sympathetic nerves in the spleen undergo an injury and sprouting response with development of adjuvant-induced arthritis (AA), a model of rheumatoid arthritis (RA). The objective of the ...present study was to determine whether this injury and sprouting response is disease-specific or occurs in a non-specific manner similar to injury and sprouting responses following sympathectomy with specific neurotoxins. Changes in noradrenergic (NA) innervation in spleens from Lewis rats 28 days following adjuvant treatment to induce arthritis and/or local 6-hydroxydopamine (6-OHDA) treatment to destroy NA nerves were examined using immunocytochemistry for tyrosine hydroxylase (TH). We observed significant increases in sympathetic innervation of hilar regions, sites of nerve entry into the spleen, and a striking decline in innervation of splenic regions distant to the hilus in arthritic compared to non-arthritic rats. While increased hilar and decreased distal NA innervation in arthritic rats was strikingly similar to that of non-arthritic 6-OHDA-treated rats, there were differences in splenic compartments innervated by sympathetic nerves between these groups. In 6-OHDA-treated rats, NA nerves re-innervated splenic compartments normally innervated by sympathetic nerves. In arthritic rats, sympathetic nerves returned to normally innervated splenic compartments, but also abundantly innervated red pulp. These findings suggest that splenic sympathetic nerves undergo a disease-associated injury/sprouting response with disease development that alters the normal pattern and distribution of NA innervation. The altered sympathetic innervation pattern is likely to change NA signaling to immune cell targets, which could exert long-term regulatory influences on initiation, maintenance, and resolution of immune responses that impact disease pathology.
We have cloned the protein coding region of an isoform of short ragweed allergen Amb a 6 (Ra6) and expressed the secreted product in Pichia pastoris at mg/l levels. 5′ RACE was performed using ...sequence obtained from a partial Amb a 6 clone. This yielded a product whose deduced protein sequence has a characteristic signal sequence motif at the N‐terminus followed by sequence consistent with that previously published for highly purified Amb a 6 Roebber et al. J Immunol 1983;131:706–11. The region encoding the secreted product was amplified by PCR and cloned into pPICZαa, an expression vector for the yeast Pichia pastoris. Yeast transformed with this vector secrete a protein which migrates near Amb a 6 in SDS–PAGE. This secreted protein reacts with polyclonal anti‐Amb a 6 antisera as well as an anti‐Amb a 6 monoclonal antibody, and has the N‐terminal sequence of Amb a 6. By time‐of‐flight mass spectrometry, recombinant Amb a 6 has a molecular weight of 9884 ± 0.2%. In addition to the deduced amino acid sequence of an Amb a 6 clone, the amino acid sequence of Amb a 6 protein is reported for comparison. The amino acid sequence was obtained by aligning overlapping tryptic and chymotryptic peptides from enzymatic digests of extensively reduced and alkylated Amb a 6. Sequences from at least three closely related Amb a 6 isoforms are present among these peptides. The amino acid sequence closely matches the deduced amino acid sequence of the Amb a 6 clone.
Abstract Aging leads to reduced cellular immunity with consequent increased rates of infectious disease, cancer, and autoimmunity in the elderly. The sympathetic nervous system (SNS) modulates innate ...and adaptive immunity via innervation of lymphoid organs. In aged Fischer 344 (F344) rats, noradrenergic (NA) nerve density in secondary lymphoid organs declines, which may contribute to immunosenescence with aging. These studies suggest there is SNS involvement in age-induced immune dysregulation. The purpose of this study was to longitudinally characterize age-related change in sympathetic innervation of the spleen and sympathetic activity/tone in male Brown Norway (BN) rats, which live longer and have a strikingly different immune profile than F344 rats, the traditional animal model for aging research. Splenic sympathetic neurotransmission was evaluated between 8 and 32 months of age by assessing (1) NA nerve fiber density, (2) splenic norepinephrine (NE) concentration, and (3) circulating catecholamine levels after decapitation. We report a decline in NA nerve density in splenic white pulp (45%) at 15 months of age compared with 8-month-old (M) rats, which is followed by a much slower rate of decline between 24 and 32 months. Lower splenic NE concentrations between 15 and 32 months of age compared with 8M rats were consistent with morphometric findings. Circulating catecholamine levels after decapitation stress generally dropped with increasing age. These findings suggest there is a sympathetic-to-immune system dysregulation beginning at middle age. Given the unique T-helper-2 bias in BN rats, altered sympathetic-immune communication may be important for understanding the age-related rise in asthma and autoimmunity.
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