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 as focused on neural-immune modulation in secondary lymphoid organs, and have 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.

Lens epithelium-derived growth factor p75 (LEDGF/p75) is a nuclear autoantigen in atopic disorders implicated in cellular protection against stress-induced apoptosis. We observed that LEDGF/p75 was cleaved during apoptosis into fragments of 65 and 58 kD generated by caspases-3 and -7 cleaving at three sites: DEVPD 30 ;G, DAQD 486 ;G and WEID 85 ;N. Sequence analysis revealed that the DEVPD 30 ;G and WEID 85 ;N sites lie within the highly conserved HATH (homologous to amino terminus of hepatoma-derived growth factor) region, also known as PWWP domain. Alignment of proteins containing this domain failed to reveal conservation of the DEVPD 30 ;G and WEID 85 ;N sites, suggesting that the HATH/ PWWP domain of LEDGF/p75 may be specifically targeted by caspases. Overexpression of LEDGF/p75 protected HepG2 cells from serum starvation-induced cell death, whereas expression of the 65 kD fragment failed to protect. The apoptotic cleavage of LEDGF/p75 may contribute to the pathogenesis of atopic disorders by abrogating its prosurvival function and enhancing its immunogenicity. Cell Death and Differentiation (2002) 9, 915 ± 925.

Objective Specific autoantigens targeted in systemic autoimmunity undergo posttranslational modifications, such as cleavage, during cell death that could potentially enhance their immunogenicity. In light of the increasing interest in the immunologic consequences of defective clearance of apoptotic cells, we sought to determine whether autoantigens cleaved during apoptosis undergo an additional wave of proteolysis as apoptosis progresses to secondary necrosis in the absence of phagocytosis. Methods Apoptosis was induced in Jurkat cells with etoposide, anti‐Fas antibody, or staurosporine (STS), and in HeLa cells with STS. Progression to secondary necrosis was assessed morphologically and quantified by trypan blue uptake. Autoantigen proteolysis during cell death was examined by immunoblotting of cell lysates using highly specific human autoantibodies as detecting probes. Results Cells treated with the different apoptosis inducers underwent a rapid apoptosis that gradually progressed to secondary necrosis. During the initial apoptotic stages, several autoantigens, including poly(ADP‐ribose) polymerase, topoisomerase I (or Scl‐70), SSB/La, and U1–70 kd, were cleaved into their signature apoptotic fragments. Progression of apoptosis to secondary necrosis was associated with additional proteolysis of these and other autoantigens in a caspase‐independent manner. Some autoantigens (e.g., ribosomal RNP, Ku, and SSA/Ro) appeared to be resistant to proteolysis during cell death. Conclusion In the absence of phagocytosis, apoptotic cells may undergo secondary necrosis, a process associated with additional proteolytic degradation of specific autoantigens. Secondary necrosis may occur in vivo in autoimmune disorders associated with impaired clearance of apoptotic cells and serve as a source of modified forms of specific autoantigens that might stimulate autoantibody responses under proinflammatory conditions.

Objective. Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation. These autoantibodies recognize topo I and fragments of this autoantigen generated during apoptosis and necrosis. We undertook this study to determine whether lysosomal cathepsins are involved in topo I fragmentation during necrosis.Methods. Topo I cleavage during necrosis was assessed by immunoblotting of lysates from L929 fibroblasts exposed to tumor necrosis factor ␣ (

Aging is associated with reduced cellular immunity, which leads to increased rates of infectious disease, cancer and autoimmunity in the elderly. Previous findings from our laboratory revealed an age-related decline in sympathetic innervation of immune organs that affects immunity. These studies suggested potential sympathetic nervous system involvement in age-induced immune dysregulation. Objectives: The purpose of this study was to longitudinally characterize the effects of age on sympathetic neurotransmission in the spleen and net sympathetic activity/tone in male Fischer 344 rats. Methods: Splenic sympathetic neurotransmission was evaluated between 8 and 24 months of age by (1) splenic norepinephrine (NE) concentration and turnover, (2) β-adrenergic receptor (β-AR) expression and (3) β-AR-stimulated splenocyte cAMP production. Measures of sympathetic neurotransmission were correlated with age-related changes in Concanavalin A (Con A)-stimulated splenocyte proliferation. Results: Splenic NE turnover increased during middle age, then subsequently declined by 18 months of age compared with 8-month-old controls (young). Splenic NE concentration increased at 10 months and decreased at 18–24 months, compared with young rats; however, plasma NE levels were not affected by age. Plasma epinephrine levels were decreased at 24 months. NE synthesis blockade increased and decreased the rate of plasma catecholamine depletion in middle and old age, respectively. β-AR-stimulated cAMP production increased in splenocytes by 15 months. An age-related decrease in Con A-induced splenocyte proliferation was apparent by 10 months and persisted through 24 months. The decline in Con A-induced splenocyte proliferation correlated with the age-related increase in cAMP production. Conclusions: Aging alters sympathetic nervous system metabolism in the spleen to affect β-AR signaling to splenocytes, suggesting that altered sympathetic-immune modulation changes are evident by early middle age.