Mortality among African American women with sarcoidosis: data from the Black Women's Health Study.

BACKGROUND: Sarcoidosis is a chronic systemic granulomatous disease of unknown etiology that disproportionately affects black females.  Few studies have specifically addressed causes of death in this population. OBJECTIVES: To assess rates and causes of death among women with sarcoidosis in a prospective cohort study of U.S. black women. DESIGN: The Black Women's Health Study is a follow-up study of 59,000 U.S. black women aged 21-69 (median age 38) at entry in 1995.  Data on demographic and lifestyle factors and medical conditions, including sarcoidosis, were obtained through biennial questionnaires.  Deaths and causes of death from 1995 through 2009 among study subjects were identified from National Death Index data. We assessed mortality rates among women with and without a history of sarcoidosis.  Poisson regression models were used to estimate age-adjusted mortality rates. Cox proportional-hazards models were used to estimate hazard ratios for mortality and 95% confidence intervals. RESULTS: A total of 121 deaths occurred among 1,192 women with a history of sarcoidosis and 2813 deaths among women without sarcoidosis.  Mortality was greater at every age among women with sarcoidosis and the overall multivariable-adjusted hazard ratio was 2.44 (95% CI 2.03-2.93, p<0.0001). Of the deaths among women with sarcoidosis, 24.7% were directly attributable to sarcoidosis. CONCLUSIONS: In the Black Women's Health Study, women with sarcoidosis were more than twice as likely to die as women without the disease, with many of the deaths directly attributable to sarcoidosis.  Sarcoidosis is an important cause of premature death among black women with the disease.

Fine-mapping in African-American women confirms the importance of the 10p12 locus to sarcoidosis.

Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single-nucleotide polymorphisms (SNPs) located in the intergenic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in these regions with sarcoidosis risk in African-American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Women's Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 intergenic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (odds ratio=0.52; P=0.01). Both SNPs are located inside an ∼300 kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller linkage disequilibrium block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~8 kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.

Abnormal pulmonary granuloma formation in osteopontin-deficient mice.

Osteopontin is a novel cytokine that is expressed in pulmonary granulomatous disease such as sarcoidosis and tuberculosis. It can regulate macrophage and T cell migration, activation, and cytokine expression, yet its role in granuloma formation and evolution is unknown. We induced hypersensitivity pulmonary granulomas by embolizing Schistosoma mansoni eggs to the lungs of osteopontin-deficient (null mutant) mice and osteopontin-sufficient (wild-type control) mice. Granulomas from osteopontin-null animals were smaller at early time points and contained remarkably few macrophages and macrophage-derived epithelioid cells and giant cells. T cell accumulation was unaffected by osteopontin deficiency. These results demonstrate that osteopontin regulates macrophage accumulation during pulmonary granuloma formation, and may explain the impaired ability of osteopontin-deficient hosts to control mycobacterial disease.

Is psychotherapy more effective when therapists disclose information about themselves?

Theorists have long debated the wisdom of therapists disclosing personal information during psychotherapy. Some observers have argued that such therapist self-disclosure impedes treatment, whereas others have suggested that it enhances the effectiveness of therapy. To test these competing positions, therapists at a university counseling center were instructed to increase the number of self-disclosures they made during treatment of one client and refrain from making self-disclosures during treatment of another client. Analyses revealed that clients receiving psychotherapy under conditions of heightened therapist disclosure not only reported lower levels of symptom distress but also liked their therapist more. Such findings suggest that self-disclosure by the therapist may improve both the quality of the therapeutic relationship and the outcome of treatment.

Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells.

Osteopontin is an RGD-containing bone matrix protein with cytokine-like functions that is associated with early stages of Th1-mediated diseases. Although the function of osteopontin in these responses is unknown, it is expressed by activated T cells and macrophages and can costimulate T cell proliferation. Studies have demonstrated that early IL-12 and IFN-gamma expression is required to induce a protective response to many intracellular pathogens. Herein, we demonstrate that osteopontin stimulation augments the ability of anti-CD3 monoclonal antibody to induce CD40 ligand (CD40L) and IFN-gamma expression on human T cells, resulting in CD40L- and IFN-gamma-dependent IL-12 production in vitro. These findings suggest a functional role for osteopontin in early Th1 responses, namely regulation of T cell-dependent IL-12 production. Further, osteopontin up-regulation of CD40L provides mechanistic support for the association of osteopontin with polyclonal B cell proliferation and humoral autoimmune disease.

Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection.

Osteopontin (OPN) is a protein that is expressed in chronic inflammatory diseases including tuberculosis, and its deficiency predisposes to more severe mycobacterial infections in mice. However, no reports have identified altered OPN expression in, or correlated these alterations to, infections in humans. The data presented herein identify alterations in the tissue expression of OPN protein and describe an inverse correlation between these levels and disease progression after inoculation of Mycobacterium bovis bacillus Calmette-Guérin vaccine in humans. Patients with regional adenitis and good clinical outcomes had abundant OPN in infected lymph nodes. This pattern of OPN accumulation was also observed in patients infected by M. avium-intracellulare. In contrast, patients with disseminated infection and histologically ill-defined granulomas had no significant osteopontin accumulation in infected lymph nodes; these patients had either deficiencies in the interferon-gamma receptor 1 or idiopathic immune defects. The level of OPN protein expression was inversely correlated with disseminated infection and, of particular interest, with death of the patient. We conclude that osteopontin expression correlates with an effective immune and inflammatory response when humans are challenged by a mycobacterial infection and that osteopontin contributes to human resistance against mycobacteria.

Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation.

Osteopontin (Opn) is a secreted adhesive, glycosylated phosphoprotein that contains the arginine-glycine-aspartic acid (RGD) cell-binding sequence that is found in many extracellular matrix (ECM) proteins (for a review of Opn see References Denhardt & Guo 1993; Patarca et al. 1993; Rittling & Denhardt 1999). Since its initial description in 1979 as a secreted protein associated with malignant transformation, Opn has been independently discovered by investigators from diverse scientific disciplines, and has been associated with a remarkable range of pathologic responses. Opn is an important bone matrix protein, where it is thought to mediate adhesion of osteoclasts to resorbing bone. However, studies from the past decade have identified an alternative role for Opn as a key cytokine regulating tissue repair and inflammation. Recent work by our laboratory and that of others has underlined the importance of Opn as a pivotal cytokine in the cellular immune response. Despite this Opn is not well known to the immunologist. In this review we will focus on studies that pertain to the role of Opn in cell-mediated and granulomatous inflammation.

Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin.

Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host protection in a mouse model of mycobacterial infection. When infected with Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria. The OPN-null mice had greater granuloma burdens consistent with the elevated bacterial load. The ability of osteopontin to facilitate the clearance of mycobacteria was most pronounced early after infection and appeared to be independent of known mediators of resistance to infection by mycobacteria: antigen-specific T-cell immunity, gamma interferon production, and nitric oxide production. BCG grew more rapidly in macrophages derived from OPN-null mice than in those from wild-type mice, demonstrating that the null phenotype was due to an intrinsic macrophage defect. These results indicate that osteopontin augments the host response against a mycobacterial infection and that it acts independently from other antimycobacterial resistance mechanisms.

Osteopontin is associated with T cells in sarcoid granulomas and has T cell adhesive and cytokine-like properties in vitro.

Sarcoidosis is a systemic disease characterized by the accumulation of activated T cells and widespread granuloma formation. In addition, individual genetic predisposition appears to be important in this disease. Osteopontin, a noncollagenous matrix protein produced by macrophages and T lymphocytes, is expressed in the granulomas of tuberculosis, and is associated with genetic susceptibility to intracellular infection. The function of osteopontin in these T cell-mediated responses is unknown. We sought to elucidate the role of osteopontin in granulomatous inflammation by characterizing its expression in different stages of sarcoidosis and its effector function on T cells in vitro. Lymphocyte-associated expression of osteopontin in sarcoidosis was demonstrated by immunohistochemistry, and its expression correlated with granuloma maturity. In addition, osteopontin induced T cell chemotaxis, supported T cell adhesion (an effect enhanced by thrombin cleavage of osteopontin), and costimulated T cell proliferation. These results suggest a novel mechanism by which osteopontin and thrombin modulate T cell recruitment and activation in granulomatous inflammation.

Tissue and T cell distribution of precursor and mature IL-16.

IL-16 is a novel cytokine, which is chemoattractant for CD4+ T cells, macrophages, and eosinophils. Recently, it was reported that IL-16 is synthesized as an approximately 80-kDa precursor molecule, pro-IL-16. Since little is known about the processing and tissue distribution of IL-16 and pro-IL-16, we investigated the distribution of IL-16 mRNA and protein in human lymphoid tissue. Northern blotting identified IL-16 mRNA predominantly in normal lymphoid organs, including PBMC, spleen, and thymus. Immunohistochemistry of human lymph node localized IL-16 protein to lymphocyte cytoplasm within T cell zones and occasionally in lymphocytes in B cell zones. Flow cytometric detection of intracellular IL-16 showed that >70% of CD4+ and CD8+ T cells constitutively expressed IL-16 protein. Western blot analysis of PBMC revealed nearly all of this protein to be approximately 80-kDa pro-IL-16 in unstimulated PBMC, and upon cell activation, the amino terminus of pro-IL-16 is processed into multiple fragments. These results show that pro-IL-16 is widely and constitutively expressed and suggest that the amino terminus of the protein can be processed upon cell activation.

Pain following human brachial plexus injury with spinal cord root avulsion and the effect of surgery.

Brachial plexus injury leading to spinal cord root avulsion in humans produces a characteristic constant crushing and intermittent shooting pain, which is often intractable. Preliminary observations suggested that this pain might be alleviated after successful nerve transfers to restore limb function. We therefore studied a group of 14 patients prospectively, to establish the validity of this observation, and to elucidate the underlying mechanisms. We found a strong correlation and temporal relationship between reduction in pain and successful nerve repair. All five patients with motor recovery experienced significant relief of de-afferentation pain, while in the seven patients with persistent pain, none had motor recovery. There was no correlation between pain relief and the minimal recovery of sensation in some cases, and no case had any return of sensory or sympathetic cutaneous axon-reflexes. While skin sympathetic axon-reflexes were reduced with T1 root lesions, there was no relationship between T1 root damage and pain. It was concluded that nerve repair can reduce pain from spinal root avulsions and that the mechanism may involve successful regeneration, and/or restoration of peripheral connections prior to their function, possibly in muscle.

In vitro transendothelial migration of blood T lymphocytes from HIV-infected individuals.

OBJECTIVE: We hypothesized that differential extravasation of circulating CD4+ or CD8+ T lymphocytes contributes to HIV-associated CD8+ lymphocytic alveolitis. Differences in T-cell transendothelial migration may be intrinsic or emerge at sites where vascular endothelium is activated by overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. DESIGN: We used an in vitro model of lymphocyte extravasation to assess transendothelial migration of peripheral blood mononuclear cells (PBMC) from HIV-positive individuals. We assayed bronchoalveolar lavage (BAL) fluid from HIV-positive and normal individuals to determine if increased levels of TNF-alpha and IFN-gamma were present in the lungs of HIV-infected individuals. METHODS: Transendothelial migration was assessed by determining the number and flow cytometric phenotype of PBMC adherent to or migrating across unstimulated or TNF-alpha and IFN-gamma-activated endothelial cell monolayers. We measured BAL fluid cytokine concentrations using standard antigen-capture enzyme-linked immunosorbent assays for TNF-alpha and IFN-gamma. RESULTS: T cells migrating across unactivated endothelial cells were significantly enriched for CD4+ T cells. Cytokine activation of endothelial cells allowed significantly greater transendothelial migration of CD8+ T cells compared to unactivated endothelial cells. TNF-alpha was increased in BAL fluid from HIV-positive individuals relative to controls. CONCLUSIONS: These data suggest that, in HIV-positive individuals, CD4+ T cells are migration competent and blood CD8+ T cells do not have enhanced migration competence relative to CD4+ T cells. CD8+ T cell extravasation is aided by TNF-alpha and IFN-gamma-induced endothelial cells activation.

A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis.

Chronic inflammation and granuloma formation are associated with mononuclear cell infiltrates and are characteristic pathologic responses in tuberculosis. To identify host cell genes involved in tuberculous pathology, we screened macrophage cDNA libraries for genes induced by mycobacterial infection. One gene isolated in this screen, osteopontin (also known as early T lymphocyte activation protein 1 or Eta-1), was of particular interest because it is a cytokine and macrophage chemoattractant. Further study revealed that Mycobacterium tuberculosis infection of primary human alveolar macrophages causes a substantial increase in osteopontin gene expression. Osteopontin protein was identified by immunohistochemistry in macrophages, lymphocytes, and the extracellular matrix of pathologic tissue sections of patients with tuberculosis. Increased osteopontin expression also was found to be associated with silicosis, another granulomatous disease. The association of osteopontin with granulomatous pathology, together with the known properties of the protein, suggest that osteopontin may participate in granuloma formation. The strategy of identifying host genes whose expression is altered by infection thus can provide valuable clues to disease mechanisms and will be increasingly valuable as additional human genome sequences become available.

Chemotactic activity of mycobacterial lipoarabinomannans for human blood T lymphocytes in vitro.

A crucial early event in tuberculosis is the ingestion of Mycobacterium tuberculosis (Mtb) by alveolar macrophages. Chemotactic factors released by infected macrophages are likely to initiate a granulomatous response, a key feature of host resistance to tuberculosis. To date, the role of mycobacterial products in regulating the granulomatous response has not been clearly defined. Here we report that the mycobacterial cell wall glycophospholipid lipoarabinomannan (LAM) could specifically induce human peripheral blood T cell chemotaxis in vitro. Both terminally mannosylated LAM isolated from Mtb and LAM lacking the terminal mannosyl units isolated from an avirulent mycobacterium could induce T cell migration in the absence of serum. In contrast, terminally mannosylated LAM isolated from Mycobacterium bovis BCG failed to induce T cell chemotaxis. These observations represent the first report that LAM is capable of directly inducing biologic responses in human T cells. Flow cytometry analysis revealed that CD4+, CD8+, and CD45RO+ lymphocytes were present in the migrating cell populations at ratios similar to those found in nonmigrating cells. The chemotactic response was found to require new protein synthesis, and could be blocked by inhibitors of protein tyrosine kinases at concentrations that did not affect random migration. Acyl groups at the reducing terminus of LAM appear to be required for the chemotactic activity of this mycobacterial glycolipid. Lastly, culture supernatants from human alveolar macrophages infected in vitro with a virulent strain of Mtb could induce T cell migration. Much of the migratory activity present in these supernatants could be blocked using a mAb against LAM, suggesting that LAM is one of the chemotactic factors released by Mtb-infected alveolar macrophages.

Migration of distinct subsets of CD8+ blood T cells through endothelial cell monolayers in vitro.

The immune response in many infections and to allografts is dependent on CD8+ cytotoxic T lymphocytes (CTL). Influx of CD8+ CTL from the blood has been documented during antigen challenge. We have previously found that a subset of CD8+ T cells from normal blood can migrate through endothelial cell monolayers in vitro. To further characterize migration-prone CD8+ T cells from normal blood, we examined the expression of CD28 and a restricted epitope of CD18/CD11a (S6F1), a CTL marker. Although normal blood CD8bright+ T cells were heterogeneous in their expression of CD28, three populations could be identified (CD28low, CD28moderate, and CD28high). CD8+ cells migrating across endothelial cell monolayers were enriched for CD8bright+ CD28high cells and a subset of CD8dim+ cells, which were CD28high. Both adherent and migrating CD8+ cells were exclusively (> 95%) S6F1high. There was also preferential adhesion and migration of CD8+ cells expressing the low-molecular-weight form of the leukocyte common antigen, CD45RO. Cytokine activation of the endothelium did not significantly alter preferential migration of these subsets. These data suggest that certain subsets of CD8+ memory T cells in normal human blood are prone to, adhere to, and migrate through allogeneic endothelial cells and would thus be likely to be recruited to sites of antigen challenge.

The lymphocyte chemoattractant factor.

The LCF is a unique interleukin without significant homology to other interleukins or chemokines. It is a chemoattractant factor for all CD4+ cells and either uses CD4 as its receptor or utilizes a cell surface complex of molecules for which there is an absolute requirement for the presence of CD4. In addition to its chemoattractant activity, it is a growth factor for CD4+ T cells, inducing resting cells to enter G1, as evidenced by the expression of MHC II molecules and IL-2R. Once induced by LCF to express IL-2R, CD4+ T cells become competent to respond to LCF and progress through the cell cycle to proliferation. LCF's activity on CD4 cells defines a role for CD4 on the eosinophil and monocyte and broadens the scope of functions of CD4 on the T cell. In this regard it may have importance in human disease states that are characterized by increased numbers of activated CD4+ cells, such as sarcoidosis, rheumatoid arthritis, or asthma. Likewise, it may play a key role in monocyte and eosinophil chemotaxis into tissues, being important in the latter in concert with hematopoietic factors that increase the available eosinophil pool.

Cytokine binding to CD4+ inflammatory cells: implications for asthma.

While LCF is present in BAL early after antigen challenge, we know little about its other potential effects beyond CD4+ T cell, monocyte, and eosinophil chemotaxis and monocyte and CD4+ T cell activation. The work described here focuses on the hypothesis that the secreted protein products of T cells participate in the airway inflammatory process that underlies human asthma, and in particular that LCF could play an early role because of the unusual responsiveness of LCF-producing T to histamine. To date, most studies have addressed the measurement of cytokines derived from CD4+ T cells (e.g., IL-2, IL-3, IL-4, IL-5, and GM-CSF) in the airways of asthmatics, and attempted to correlate the presence of protein or mRNA with the complexion of the inflammatory infiltrate. These studies have been based upon the reports that there are increased numbers of CD4+ T cells in the airways of asthmatics, and that the presence of eosinophils might correlate with the secretion of TH2-type cytokines like IL-3, -4, and -5. Using this information as a background, our work has approached the problem in an entirely different way. We have focused our attention on the early events in antigen-induced asthma that are responsible for CD4+ cell accumulation in the lung, including CD4+ T cells, eosinophils, and monocytes. We have attempted to identify mechanisms by which mast cell mediators, in particular histamine, might play a role in the secretion of chemotactic lymphokines that are selective for CD4+ cells by using CD4 itself as a chemotactic factor receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of psychological and pharmacological treatments for nocturnal enuresis.

This review provides a quantitative integration of research on the effectiveness of psychological and pharmacological treatments for nocturnal enuresis. With the use of experiments that compared treatments with either no treatment or another form of treatment, this article assesses (a) the overall effectiveness of psychological and pharmacological treatments, (b) the relative effectiveness of specific types of treatments, and (c) moderators of treatment effectiveness including investigator allegiance. Findings from the review confirm that enuretic children benefit substantially from treatment. However, more children improve from psychological than from pharmacological interventions. Moreover, psychological treatments involving a urine alarm are most likely to yield benefits that are maintained once treatment has ended.