Changes in lung immune cells related to clinical outcome during treatment with infliximab for sarcoidosis.

Pulmonary sarcoidosis is characterized by an exaggerated CD4+ T cell response and formation of non-necrotizing granulomas. Tumour necrosis factor α (TNF-α) is regarded as crucial for granuloma formation and TNF-α inhibitors offer a third-line treatment option for patients not responding to conventional treatment. However, not all patients benefit from treatment, and an optimal dose and treatment duration have not been established. Insight into the influence of TNF-α inhibitors on lung immune cells may provide clues as to what drives inflammation in sarcoidosis and improve our understanding of treatment outcomes. To evaluate the effects of treatment with the TNF-α inhibitor infliximab on lung immune cells and clinical features of the patients, 13 patients with sarcoidosis refractory to conventional treatment were assessed with bronchoalveolar lavage (BAL), spirometry and computerized tomography (CT) scan closely adjacent to the start of infliximab treatment. These investigations were repeated after 6 months of treatment. Treatment with TNF-α inhibitor infliximab was well tolerated with no adverse events, except for one patient who developed a probable adverse event with liver toxicity. Ten patients were classified as responders, having a reduced CD4/CD8 ratio, a decreased percentage of CD4+ T cells expressing the activation marker CD69 and number of mast cells (P < 0·05 for all). The percentage of T regulatory cells (Tregs ), defined as forkhead box P3+ CD4+ T cells decreased in most patients. In conclusion, six months of infliximab treatment in patients with sarcoidosis led to signs of decreased CD4+ T cell alveolitis and decreased mastocytosis in the lungs of responders.

Education, employment, absenteeism, and work disability in women with systemic lupus erythematosus.

OBJECTIVES: To study education, employment, absenteeism, and work disability (WD) in women with systemic lupus erythematosus (SLE) compared to population controls. METHOD: The study included 181 women of working age with SLE (mean age 44.0 years, disease duration 12.7 years) and 549 female population controls matched for age living in the same metropolitan area of Helsinki. Data regarding education, employment, absenteeism, and WD in patients and controls were obtained by questionnaire and personal interview. RESULTS: Basic education, vocational, or academic degrees and occupational categories in patients with SLE were similar to those in controls. In total, 62% of the patients were employed, compared to 77% of the controls (p < 0.001). During the preceding 12 months, employed SLE patients had been on sick leave for 25.4 days vs. 10.2 days in controls (p < 0.001). Subjective work ability regarding physical and mental demands of the job were lower in SLE patients than in controls (p < 0.001 and p = 0.036, respectively). The rate of permanent WD, defined as receiving disability benefits, was 34.3% in SLE patients vs. 10.3% in controls (p < 0.001). Cumulative WD due to SLE 5, 10, and 20 years after the clinical diagnosis was 13, 22, and 47%, respectively. CONCLUSIONS: SLE does not seem to affect educational achievements and the employment rate for SLE patients is reasonably high. Absenteeism and work disability are, however, 2-3 times more common than in controls. Less than half of the patients were on permanent disability pension due to SLE 20 years after diagnosis of the disease.

Frequency of and risk factors for symptomatic bone fractures in patients with systemic lupus erythematosus.

OBJECTIVES: To study risk factors for symptomatic bone fractures in patients with systemic lupus erythematosus (SLE) and to compare the frequency of fractures between SLE patients and population controls. METHOD: The study included 222 SLE patients [mean age 47.0 years, disease duration 13.1 years, 204 (92%) women] and 720 population controls living in the metropolitan area of Helsinki. The history of symptomatic bone fractures in SLE patients and controls was recorded by interview, and demographic and clinical data of SLE patients were obtained by interview, clinical examination, and chart review. RESULTS: A history of at least one symptomatic bone fracture was recorded in 93 (42%) of all 222 patients with SLE. The risk of any fracture in 204 women with SLE compared to controls was 1.8 [95% confidence interval (CI) 1.3-2.4] and fractures in the ankle, hip, and vertebral column were more common than in female controls, with odds ratios (ORs) of 2.0 (95% CI 1.1-3.7), 5.1 (95% CI 1.2-21.5), and 4.0 (95% CI 1.8-8.6), respectively. In 18 men with SLE, compared to male controls, no difference in the frequency of fractures was observed (OR 0.7, 95% CI 0.3-2.0). Risk factors for bone fractures in women with SLE were age (p = 0.008), comorbidity (p = 0.050), and the duration of corticosteroid use (p = 0.025). CONCLUSIONS: Symptomatic bone fractures, especially in the ankle, hip, and vertebral column, are common in women with SLE. Special attention should be paid to preventing fractures in elderly female patients with comorbidities and a long duration of corticosteroid use.

Reproductive health in women with systemic lupus erythematosus compared to population controls.

OBJECTIVE: To study the reproductive health history in women with systemic lupus erythematosus (SLE) compared to population controls. METHODS: A total of 206 female SLE patients were interviewed regarding demographic and disease data, menstruation, use of contraception and hormone replacement therapy (HRT), infertility, and pregnancies. The control group consisted of 1037 women from the general population of similar age and socioeconomic status living in the same region. RESULTS: In SLE women compared to population controls, mean age at menarche (13.3 vs. 13.2 years) and frequency of infertility (16% vs. 16%) were similar but menopause occurred earlier (44.9 vs. 46.8 years, p = 0.01). Current use of oral contraceptives (OCs) was less common than in controls [18% vs. 28%, odds ratio (OR) 0.55, 95% CI 0.3-1.0] while previous use of progesterone-containing intrauterine devices (IUDs) was more common (13% vs. 5%, OR 3.2, 95% CI 1.9-5.4). Current use of HRT was similar (22% vs. 21%) but SLE patients had started the use earlier (43.2 vs. 47.1 years, p = 0.003). Mean number of pregnancies was lower in SLE patients compared to controls (2.3 vs. 2.5, p = 0.046) and in lupus nephritis patients compared to SLE patients without nephritis (1.9 vs. 2.5, p = 0.01). No difference was found in the occurrence of spontaneous and induced abortions compared to controls, but pregnancy-associated complications were more common in SLE women. CONCLUSION: When compared to population controls women with SLE are normally fertile, use less OCs and more IUDs, have earlier menopause and use HRT as frequently. Family size is reduced, especially in lupus nephritis patients, and pregnancy-associated complications are more common.

Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord.

With advancing age, the incidence of neuronal atrophy and dystrophy increases and, in parallel, behavioural sensorimotor impairment becomes overt. Activated microglia has been implicated in cytotoxic and inflammatory processes in neurodegenerative diseases as well as during aging. Here we have used immunohistochemistry and in situ hybridization to examine the expression of OX42, ED1, ED2, GFAP and clusterin in CNS of young adult and behaviourally tested aged rats (30-month-old), to study the occurrence of activated microglia/ED1 positive macrophages in senescence and to what extent this correlates with astrogliosis and signs of sensorimotor impairment among the individuals. The results show a massive region-specific increase in activated microglia and ED1 expressing cell profiles in aged rats. The infiltration was most prominent in the spinal cord dorsal columns, including their sensory relay nuclei, and the outer portions of the lateral and ventral columns. At such sites the occurrence of macrophages coincided with increased levels of GFAP and positive correlations were evident between the labeling for, on the one hand, OX42 and, on the other, GFAP and ED1. Also, the ventral and dorsal roots were heavily infiltrated by ED1 positive cells. The signs of gliosis were most pronounced among aged rats with advanced sensorimotor impairment. In contrast, the grey matter of aged rats showed very few activated microglia/ED1 labeled cells despite signs of focal astrogliosis. ED2 expression was confined to perivascular cells and leptominges with a similar labeling pattern in young and aged rats. In aged rats increased expression of clusterin was observed in GFAP-immunoreactive profiles of the white matter only. It is suggested that this increase may reflect a response to degenerative/inflammatory processes.

Regulation of neurotrophin signaling in aging sensory and motoneurons: dissipation of target support?

A hallmark of senescence is sensorimotor impairment, involving locomotion and postural control as well as fine-tuned movements. Sensory and motoneurons are not lost to any significant degree with advancing age, but do show characteristic changes in gene-expression pattern, morphology, and connectivity. This review covers recent experimental findings corroborating that alterations in trophic signaling may induce several of the phenotypic changes seen in primary sensory and motoneurons during aging. Furthermore, the data suggests that target failure, and/or breakdown of neuron-target interaction, is a critical event in the aging process of sensory and motoneurons.

Increased glutathione levels in neurochemically identified fibre systems in the aged rat lumbar motor nuclei.

The spinal cord motor nuclei have been the focus of a number of investigations exploring neurodegenerative mechanisms, e.g. excitotoxicity mediated by glutamate and oxidative stress. Here, high-resolution quantitative post-embedding immunocytochemistry with antibodies to oxidized and reduced glutathione (GSH), an ubiquitously expressed scavenger of free radicals, was used to examine if GSH synthesis is upregulated pre- and/or postsynaptically in the lumbar motor nuclei of aged (30 month old) rats. The purpose was, moreover, to resolve the extent of correlation between GSH expression, transmitter identity and degenerative changes. Tissue from young adult rats was co-processed for comparison. The quantitative immunogold analysis revealed an increase in GSH-immunoreactivity in both pre- and postsynaptic compartments in the lumbar motor nuclei of aged rats. Presynaptically, the enrichment of GSH-immunoreactivity was seen in axonal boutons of normal appearance, and was furthermore restricted to the extra-mitochondrial compartment. Postsynaptically, the aged rats disclosed, in comparison with young adults, higher values for GSH-immunoreactivity both over mitochondria (+49%) and cytoplasmic matrix (+130%). When analysing the transmitter identity of the bouton profiles, it turned out that close to 50% of all glutamate-immunoreactive boutons in the aged rats contained very high levels (> 40 gold particles/microm2) of GSH-immunoreactivity. Strong GSH-immunoreactivity was also a typical feature of a subset of axon terminal- and axon fibre-like profiles in the aged rat that showed signs of axon dystrophy and degeneration. When comparing with normally appearing axon fibre profiles located in close vicinity, the population of aberrant axons had higher average levels of glutamate-immunoreactivity (+93%), and lower average levels of glycine-immunoreactivity (-88%). No difference was seen regarding the levels of GABA. The results of this study lend support to the idea that aging in the spinal cord motor nuclei is associated with an increased oxidative stress and indicate that different transmitter systems are differentially affected by the degenerative process.

Upregulation of GFRalpha-1 and c-ret in primary sensory neurons and spinal motoneurons of aged rats.

Aging is associated with a decline in neuromuscular and somatosensory functions. Senile muscle atrophy, considered to be of neurogenic origin, is prevalent, and sensory thresholds increase with age. However, the loss of motoneurons and primary sensory neurons is small, while sensory and motor innervation appears disturbed due to aging-related axon lesions. One mechanism which may play a role in this process is altered trophin signaling. We here report that the glial cell line-derived neurotrophic factor (GDNF) receptor GFRalpha-1 mRNA and GFRalpha-1 protein-like immunoreactivity are upregulated in spinal motoneurons, and in dorsal root ganglion neurons of 30-month-old rats. The established signaling mechanism for the GDNF/GFRalpha-1 complex is through binding to the tyrosine kinase receptor encoded by the c-ret proto-oncogene, and we also show here that c-ret mRNA is upregulated in both motoneurons and primary sensory neurons of aged rats. The findings reported here, combined with evidence presented in other studies of changes in p75(NTR) and trk receptor expressions in aging primary sensory neurons and motoneurons, point at marked alterations in trophin signaling in senescence.

Decreased axosomatic input to motoneurons and astrogliosis in the spinal cord of aged rats.

An increasing body of evidence indicates that aging-related impairments of nervous functions are caused by damage to neuron integrity rather than by loss of neurons. By using electron microscopy, we have examined axosomatic boutons on spinal cord motoneurons derived from aged and young adult Sprague-Dawley rats. The main finding was that about half of the examined motoneuron somata from aged rats had a reduced (50%) bouton coverage, which seemed to be caused by a smaller number of axosomatic bouton profiles. Long stretches of the cell body plasma membrane were apposed by pale processes, and immunolabeling for glial fibrillary acidic protein (GFAP) disclosed that a number of the aged motoneurons appeared embedded in GFAP immunopositive processes. Lumbar motoneurons seemed to be more severely affected than cervical motoneurons. At the ultrastructural level, affected motoneurons disclosed plasma membrane irregularities with appendages/sprout-like extensions that in some cases were sites for axosomatic contacts.