Inflammatory Mediators

The known CNS effects of inflammatory cytokines regulated by interferon include behavioral disturbances. For example, interleukin (IL)-1 can induce slow-wave sleep, loss of appetite, and enhanced production of corticotrophin releasing hormone (CRH).

In patients with hepatitis C infection (HCV), the severity of depressive symptoms is correlated with expression of proinflammatory cytokines.106 A variety of inflammatory cytokines and chemokines, including IL2, IL6, IL10, interferon-alpha (IFN-a), and tumor necrosis factor-alpha, as well as metalloproteinase-9, are potential triggers of neuronal cell activation.107 Intrathecal production of proinflammatory cytokines could be stimulated by locally produced or circulating autoantibodies, and peripherally generated cytokines may mediate behavioral symptoms through passage of cytokines through leaky regions in the blood-brain barrier or through active transport and trans mission of cytokine signals via afferent nerve fibers.108

Studies of autoimmune disease in animal models have suggested a pathogenic role for both autoantibody production and intrathecal production of inflammatory cyto kines in the pathogenesis of nervous system disorders.109 Behavioral changes and cognitive dysfunction are well described in several animal models of spontaneous autoimmune disease.110-112 The deficits in hippocampal learning and memory, which occur in autoimmune mice, are similar to the cognitive disturbances found in patients with SLE and SS.113,114 In the animal models of chronic autoimmune disease, cognitive dysfunction develops early in the absence of gross CNS damage.112,113 Up-

regulation of the hippocampal immune system, resulting in microglial production of inflammatory cytokines, has been demonstrated in mice with spontaneous autoim mune disease.115 In animals, chronic inflammatory stress results in damage to hippocampal neurons, as does anti-DNA antibody, which preferentially binds to hip-pocampal neurons and causes neuronal death with resulting cognitive dysfunction.

IFN-a administration is commonly associated with a spectrum of neuropsychologic effects, including fatigue, vegetative symptoms (sleep disorder, psychomotor slowing, and anorexia), and affective disorders (anxiety and depression), in addition to cognitive effects and profound cerebral dysfunction. In cancer patients undergoing IFN-a therapy, a well described syndrome of IFN-mediated fatigue followed by depression occurs and progresses to coma if INF-a therapy is continued.116 A similar syndrome of fatigue, cognitive dysfunction, and depression is associated with IFN-a therapy of chronic hepatitis C liver disease.117

The psychopathology associated with interferon treatment is hypothesized to be in part mediated by pro-inflammatory cytokines (IL-1, IL-6) induced by IFN-a.118 Animal data support a role for IFN-a in mediating behavioral changes. IFN-a has effects on intracerebral proinflammatory cytokine production and activation of corticotrophin releasing factor (CRF) production, leading to dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). In humans, acute administration of IFN-a robustly activates the HPA axis via enhanced production of CRF.119 Additionally, it has been reported that those melanoma patients who develop major depression while undergoing IFN-a therapy have significantly higher responses of corticotropin and cortisol.120 These data, however, are inconsistent with data regarding pituitary-adrenal axis function in pSS. Johnson and colleagues121 assessed pituitary and adrenal function in eight pSS subjects with anxiety (seven out of eight) and depression (three out of eight) and eight healthy controls. Significantly lower corticotropin and cortisol levels, as well as a lack of response to CRH, was found in the pSS patients, suggesting hypofunction rather than hyperfunction of the HPA axis.

IFN-a is also hypothesized to mediate depression by enzymatic effects on the rate-limiting step of tryptophan (TRP) conversion into kynurenine, thereby reducing availability of TRP conversion into serotonin. Intra-cerebroventricular injection of IFN-a in animals results in depletion of TRP, the primary precursor of serotonin, and is correlated with depression.122 Studies in human beings have demonstrated that INF-a induced changes in TRP metabolism are related to depression.123 Serotonin and CRF pathways may converge in mediating mood and cognitive symptoms, as the vegetative and somatic symptoms during IFN-a treatment correlated with effects on CRF pathways, whereas mood and cognitive symptoms correlated with the magnitude of TRP depletion in plasma.120

Evidence linking IFN-a with neuropsychiatry symptoms in cancer and HCV suggests a potential role for interferon inducible inflammatory cytokines in mediating the cognitive and affective disorders in medically ill patients, particularly persons with rheumatic disorders; however, the data exploring the relationship between neuropsychiatry symptoms and IFN-a or inflammatory cytokines in autoimmune disease are very limited. Levels of IFN-a were increased in the CSF of five of six patients with lupus psychosis, and in four of these five patients, the levels in CSF were higher than those in serum. IFN-a levels decreased when the manifestations of lupus psychosis subsided.124 Investigators in the Division of Rheumatic and Autoimmune disease at the University of Minnesota have demonstrated abnormal regulation of type I interferon (IFN-a) inducible genes in association with both SLE and with SS.125,126 Three molecules in the inflammatory IL-1 cytokine pathway regulated by interferon were over-expressed: IL-1 b, the IL-1 receptor, and the IL-1 receptor antagonist. One group recently reported that increased expression of the interferon gene signature in peripheral blood mononuclear cells correlates with anti-Ro/SSA antibody titer.127 However, a recent study, which examined the relationship between fatigue and concurrent immunologic status in pSS, did not support the hypothesis of a causative role for IFN-induced cytokines in that fatigue was equally prevalent among seronegative and seropositive patients.31 Whether CSF levels of inflammatory cytokines are higher in pSS patients with vegetative symptoms or depression, or whether TRP concentrations are reduced in plasma of pSS patients with depression, is unknown.

Cellular Autoimmunity

Hypothetical mechanisms of cell-mediated autoimmunity of potential relevance to pSS are (1) imbalance between autoimmune effector and regulatory T cells and (2) genetically determined (ie, intrinsic) abnormality in T-cell activation, resulting in loss of tolerance to neural autoantigens. Histopathologic examination in patients with sensory neuronopathy has demonstrated mononuclear infiltration of dorsal root ganglia.62,63 Electrophysiologic studies have tended to support the concept of a sensory ganglionopathy, specifically with involvement of the neuronal cell body as opposed to the axon or root in patients with SS and sensory neuronopathy. Activation of endogenous neuropeptides in nerve fibers, as well as up-regulated expression of neuropeptides in mast cells, plasma cells, and lymphocytes, has also been suggested as a possible mechanism of dorsal root ganglionopathy.128,129

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