The neurological complications of systemic sarcoidosis.

Involvement of the central nervous system in sarcoidosis arises predominantly due to infiltration of the meninges leading to pachymeningitis with cranial neuropathies, hydrocephalus, encephalopathy and hypothalamic dysfunction. Less frequently cerebral mass lesions occur, and spinal cord lesions have been reported. Involvement of the peripheral nervous system leading to radiculopathies, peripheral neuropathy and mononeuritis multiplex also occurs and muscle involvement may be difficult to diagnose until advanced stages. If neurological syndromes arise in patients with established biopsy proven systemic sarcoidosis, the diagnosis is usually easy to make, but oftentimes patients may present de novo with neurological symptoms and signs without systemic involvement. Subsequent investigations may lead on to the identification of systemic granulomata, but on other occasions these are not found; it has not yet been established what relationship such cases has to those with the systemic disorder in whom neurological complications arise.

Nuclear factor-kappaB activation in alveolar macrophages requires IkappaB kinase-beta, but not nuclear factor-kappaB inducing kinase.

Cytokine mediated activation of alveolar macrophages (AMs) is an important event in the pathogenesis of fibrosing alveolitis (FA). Through membrane-associated antigens, cytokines (e.g., tumor necrosis-factor-alpha and interleukin-1) are believed to activate a common kinase cascade that initiates the cytoplasmic degradation of IkappaB and nuclear translocation of "nuclear factor-kappaB" (NF-kappaB). In the nucleus, NF-kappaB promotes the transcription of genes encoding chemokines and cytokines involved in chronic inflammation. Preventing cytokine-mediated NF-kappaB activation is a potential strategy for attenuating the lung injury that occurs in FA. Previously, we have demonstrated that, unlike AMs from healthy volunteers, AMs from patients with inflammatory lung diseases express the coxsackie/adenovirus receptor and the alphav integrins required for adenovirus (Adv) infection. This property allows Adv-mediated transgene delivery to diseased, but not normal, AMs and analysis of molecular pathways involved in gene transcription. In this study, AMs were infected with Adv constructs expressing a defective beta subunit of IkappaB kinase (AdvIKKbetakd) and a defective NF-kappaB inducing kinase (AdvNIKkd) to investigate the contribution of these molecules to NF-kappaB activation. We observed that IKKbeta, but not NIK, was required for NF-kappaB activation. The results of this study identify IKKbeta, but not NIK, as a potential therapeutic target in diseases that involve NF-kappaB-dependent gene transcription.