Antibody Response to Paramyxoviruses in Paget's Disease of Bone.

Paget's disease of bone (PDB) is a common skeletal disorder characterised by focal abnormalities of increased and disorganised bone turnover. Genetic factors play a central role in the pathogenesis of PDB but environmental factors also contribute. Measles virus (MV), respiratory syncytial virus (RSV) and canine distemper virus (CDV) have all been implicated as potential disease triggers but the data are conflicting. Since chronic paramyxovirus infection with measles is known to be accompanied by increased production of antiviral antibodies, we have analysed circulating concentrations of antibodies to MV, CDV, and RSV as well as mumps, rubella and varicella zoster virus (VZV) in 463 patients with PDB and 220 aged and gender-matched controls. We also studied the relation between viral antibody concentrations and various markers of disease severity and extent in 460 PDB patients. A high proportion of cases and controls tested positive for antiviral antibodies but there was no significant difference in circulating antibody concentrations between PDB cases and controls for MV, CDV, RSV, rubella or VZV. However, mumps virus antibody levels were significantly higher in the PDB cases (mean ± SD = 3.1 ± 0.84 vs. 2.62 ± 0.86. p < 0.001). There was no association between disease severity and circulating antibody concentrations to any of the viruses. In conclusion, we found no evidence to suggest that PDB is associated with abnormalities of immune response to measles or other paramyxoviruses, although there was evidence of a greater antibody response to mumps. The results do not support that hypothesis that PDB is associated with a persistent infection with measles or other paramyxoviruses.

Cellular Functions of Optineurin in Health and Disease.

Optineurin (OPTN) was initially identified as a regulator of NF-κB and interferon signaling, but attracted most attention because of its association with various human disorders such as glaucoma, Paget disease of bone, and amyotrophic lateral sclerosis. Importantly, OPTN has recently been identified as an autophagy receptor important for the autophagic removal of pathogens, damaged mitochondria, and protein aggregates. This activity is most likely compromised in patients carrying OPTN mutations, and contributes to the observed phenotypes. In this review we summarize recent studies describing the molecular mechanisms by which OPTN controls immunity and autophagy, and discuss these findings in the context of several diseases that have been associated with OPTN (mal)function.

Regulation of TBK1 activity by Optineurin contributes to cell cycle-dependent expression of the interferon pathway.

The innate immune system has evolved to detect and neutralize viral invasions. Triggering of this defense mechanism relies on the production and secretion of soluble factors that stimulate intracellular antiviral defense mechanisms. The Tank Binding Kinase 1 (TBK1) is a serine/threonine kinase in the innate immune signaling pathways including the antiviral response and the host defense against cytosolic infection by bacteries. Given the critical roles of TBK1, important regulatory mechanisms are required to regulate its activity. Among these, Optineurin (Optn) was shown to negatively regulate the interferon response, in addition to its important role in membrane trafficking, protein secretion, autophagy and cell division. As Optn does not carry any enzymatic activity, its functions depend on its precise subcellular localization and its interaction with other proteins, especially with components of the innate immune pathway. This review highlights advances in our understanding of Optn mechanisms of action with focus on the relationships between Optn and TBK1 and their implication in host defense against pathogens. Specifically, how the antiviral immune system is controlled during the cell cycle by the Optn/TBK1 axis and the physiological consequences of this regulatory mechanism are described. This review may serve to a better understanding of the relationships between the different functions of Optn, including those related to immune responses and its associated pathologies such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget's disease of bone.

Paget's disease of bone: an osteoimmunological disorder?

Osteoimmunology represents a large area of research resulting from the cross talk between bone and immune systems. Many cytokines and signaling cascades are involved in the field of osteoimmunology, originating from various cell types. The RANK/receptor activator of nuclear factor Kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling has a pivotal role in osteoimmunology, in addition to proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17. Clinically, osteoimmunological disorders, such as rheumatoid arthritis, osteoporosis, and periodontitis, should be classified according to their pattern of osteoimmunological serum biomarkers. Paget's disease of bone is a common metabolic bone disorder, resulting from an excessively increased bone resorption coupled with aberrant bone formation. With the exception of the cellular responses to measles virus nucleocapsid protein and the interferon-gamma signature, the exact role of the immune system in Paget's disease of bone is not well understood. The cytokine profiles, such as the increased levels of IL-6 and the interferon-gamma signature observed in this disease, are also very similar to those observed in other osteoimmunological disorders. As a potential osteoimmunological disorder, the treatment of Paget's disease of bone may also benefit from progress made in targeted therapies, in particular for receptor activator of nuclear factor Kappa-B ligand and IL-6 signaling inhibition.

An atypical presentation of Paget's disease in an immunocompromised individual. A case report.

Paget's disease of bone is a localized disorder of bony resorption. The mechanism underlying the development of the disease remains controversial. There is substantial evidence suggesting a genetic basis for Paget's disease in some patients. A viral etiology of Paget's disease has been advocated. A further hypothesis implicating an immunological mechanism for this disease is based on growing evidence reviewed in the text. The presented case showed clinical and X-ray features typical of a very aggressive form of Paget's disease. We hypothesize that the extreme local aggressiveness of this case was secondary to the patient's concomitant immunosuppression due to an extended therapy following renal transplant.

[Epidemiology of Paget's disease. Peculiarities in the province of Zamora]. / Epidemiología de la enfermedad de Paget. Peculiaridades en la provincia de Zamora.

BACKGROUND: Some paramyxovirus (measles, respiratory syncytial virus, and dog's distemper virus) are currently considered to be responsible for Paget's disease of the bone. A relevant role is also given to inheritance as predisposing factor. Some authors have found an association between HLA antigens with this disease, but without unanimous agreement. Although this hypothesis of an interaction between a genetic factor and a viral infectious agent is the most accepted universally, there is not yet a definitive cause for the disease. The participation of some other environmental factors has not been ruled out. METHODS: One hundred and forty patients in the Zamora province were studied. The geographic distribution in the different areas of the province was analyzed and also whether there was family aggregation all cases. HLA-I was determined in 59 patients and HLA-II in cases with aggregation. The mineral composition (calcium, fluorine, magnesium, nitrates, and chlorine) analysis of public running water was carried out in all population centers in the province. RESULTS: Aggregation was found in four families (four, two, four, and three siblings, respectively). Although HLA-I antigens were determined in 59 patients, no association was found. HLA-II antigens were also determined in the involved patients with family links and no association was found between these antigens and the disease. A much higher aggregation was found in some particular areas in our province and these foci coincided with some characteristics of mineral composition of public running waters. CONCLUSIONS: There is a genetic factor predisposing to the disease, as family aggregation occurs with a higher frequency than would otherwise be expected. Nevertheless, no association with HLA antigens was found. This disease is more common in some particular geographic areas, thus supporting the hypothesis of an environmental factor as trigger. An association was found between mineral composition of public running waters and patient geographic distribution.

Cellular immunity aspects in elderly subjects with Paget's disease of bone.

The etiology and pathophysiology of Paget's disease of bone are not yet entirely defined. There is evidence suggesting the participation of the immune system in the pathophysiology of this disease. Hence, we examined T cell mitogenic proliferation, NK cell activity, T cell subsets, interleukin-1 (IL-1), and interleukin-6(IL-6) production by peripheral mononuclear cells and IL-6 levels in the peripheral blood sera of 17 Paget's patients aged (74.5 +/- 2.4 years) and of 17 elderly control subjects (74.7 +/- 2.2 years). Pagetic patients were found to have immunological parameters not significantly different from those of the elderly control group. Moreover, the results obtained from Paget's patients with the active form of the disease did not differ from those of patients with inactive disease. Therefore, at least on the basis of the parameters used in this study, it is possible to conclude that the cellular immunity of Paget's patients is not different from that of elderly control subjects and that the role of IL-1 and IL-6 in this disease should be reviewed.

Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate.

Bisphosphonates suppress bone resorption and are used in the management of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, there is a transient febrile reaction and transient hematological changes suggestive of an acute phase response. Because IL-6 is considered to be an important mediator of the acute phase response, we examined the changes in circulating IL-6 bioactivity in 38 patients with Paget's disease treated with the nitrogen-containing bisphosphonate (3-dimethyl-amino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients who had never received such bisphosphonate were treated with oral dimethyl-APD (100-400 mg/day) and 22 (9 for the first time) with intravenous dimethyl-APD 4 mg/day. Treatment was given for 10 days. Eleven of 38 patients, all first treatments, showed an increase in body temperature of more than 0.5 degrees C exceeding 37 degrees C associated with a significant decrease in lymphocyte count and an increase in serum CRP values. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulating IL-6 bioactivity increased significantly and this increase generally preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those without (128 +/- 30 vs. 31 +/- 4 U/ml, p < 0.001). The peaks in plasma IL-6 were further correlated with the peaks in temperature and in serum CRP values (r = 0.49, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical significance of antibodies against calcitonin.

Calcitonin (CT) inhibits osteoclast-mediated bone resorption and is being used to treat Paget's disease of bone, hypercalcemia of malignancy and postmenopausal osteoporosis. The formation of antibodies against heterologuous calcitonins like salmon calcitonin (sCT) is common and occurs in 40-70% of the patients treated for more than 4 months. Not all of these patients, however, develop a secondary resistance to sCT, therefore the clinical significance of sCT antibodies is discussed controversially. In vivo and in vitro approaches demonstrate a neutralizing effect in 35 to 60% of the patient sera with antibodies against sCT. These neutralizing antibodies appear to explain most cases of clinically relevant secondary resistance to sCT treatment, which occurs in 25-45% of the patients after treatment periods of 6 months and longer. A positive treatment response to human CT after development of secondary resistance to sCT proves the diagnosis of antibody related resistance. Few cases develop secondary resistance in the absence of sCT binding antibodies, the mechanism of this phenomenon is unclear. Antibody related resistance is a significant problem in long term treatment with sCT. Especially in conditions like postmenopausal osteoporosis, where no readily accessable marker of treatment response is available, the development of sCT antibodies and their possible neutralizing effect has to be considered.

[Differences in the cellular response of the immune system in patients with Paget's disease of bone after elcatonin and etidronate administration]. / Diferencias en la respuesta celular del sistema inmune en pacientes con la enfermedad ósea de Paget tras la administración de elcatonina y etidronato.

A cellular immunological defect is present in patients with Paget's disease of the bone. Low counts of CD4, high counts of CD8, and a low CD4/CD8 ratio were observed in 58 patients compared with controls. These findings were not correlated with the metabolic activity of the disease. After therapy with Elcatonine an improvement in the cellular immunological defect was observed in 15 patients. Etidronate improved the biochemical bone patterns but no changes were observed in the number of lymphocytic subpopulations. These changes can be related to the improvement in the bone metabolic disorder or be the result of an effect on the altered immunity in this disease.

[Neutralizing antibodies against salmon calcitonin. The cause of a treatment failure in Paget's disease]. / Neutralisierende Antikörper gegen Lachscalcitonin. Ursache für ein Therapieversagen bei Morbus Paget.

A 72-year-old woman with Paget's disease of the femur (increasing curvature of the femur in the last 20 years, lately with ever more pain on walking) was at first treated with salmon calcitonin, daily 400 IU nasally, for 2 years. As a result, alkaline phosphatase (AP) concentration fell from initially 703 U/l, to 401 U/l after 7 months' treatment. An increase in AP concentration was first noted after 10 months of treatment, rising after 24 months to 688 U/l. The symptoms, initially having responded rather well to therapy, markedly progressed. In parallel, titres were recorded for binding (maximally 1:100) and neutralizing antibodies (neutralizing action maximally 75%) against salmon calcitonin. Because of the development of secondary resistance to salmon calcitonin the medication was changed to human calcitonin (100 IU daily, subcutaneously). This again resulted in a fall of the AP concentration (to 319 U/l), which remained essentially unchanged (401 U/l) over a period of 17 months on 100 IU human calcitonin three times weekly.

Dogs, distemper and Paget's disease.

The cause of Paget's disease is still unknown, despite many years of intensive study. During this time, evidence has sporadically emerged to suggest that the disease may result from a slow viral infection by one or more of the Paramyxoviruses. More recently, epidemiologic and molecular studies have suggested that the canine paramyxovirus, canine distemper virus, is the virus responsible for the disease. If true, then along with rabies, this would be a further example of a canine virus causing human disease. Studies in the natural host have now supported these findings. Further investigations have proposed that the bony abnormalities seen in Paget's disease are due to the effects of the virus on osteoclastic interleukin-6 and c-FOS production, possibly via the transcription factor NF-kappa B.

Cellular immunodeficiency in Paget's disease of bone: changes induced by treatment with elcatonin.

We have found a cellular immune defect (low CD4 T lymphocyte count, high CD8 T lymphocyte count and a low CD4/CD8 ratio) in 39 PDB patients. This finding is not correlated with the bone metabolic activity of the disease. There was an improvement in the cellular immune defect in fifteen patients after treatment with elcatonin. These changes could be related to the improvement in the metabolic derangement or else could be the consequence of an effect on altered immunity.

HLA-D antigens and Paget's disease of bone.

HLA-A, -B, -C, -DR, and -DQ antigens were determined in 25 Ashkenazi Jews with Paget's disease of bone. HLA-DR2 was more frequent in the Pagetic patients compared with 57 healthy controls of the same ethnic origin. This finding concurs with a previous report and raises the possibility that HLA-DR2 may be associated with Paget's disease of bone, probably by predisposing the bone cells to viral infection.

Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of postmenopausal osteoporosis.

Nineteen patients with postmenopausal osteoporosis were treated with 200 u (15 nmol) synthetic salmon calcitonin (sCT) intranasally per day for 15 months. Six months after the start of the nasal administration of sCT, antibodies were recognized in 7, and after 15 months in 10 of the 19 patients studied. The half-maximal dilution of serum binding to 60 pmol/l [125I]sCT (dilution-50) ranged from 2 to 490, and half-maximal inhibition of [125I]sCT binding (60 pmol/l) from 91 to 221 pmol/l sCT. In a cultured breast cancer cell line (T47D) cAMP production was stimulated by sCT (EC50 70 pmol/l). Stimulated cAMP production by sCT (50 pmol/l) was reduced to between 4% and 23% in the presence of serum from patients with antibody dilution-50 of [125I]sCT binding exceeding 32. In patients with lower titer antibodies cAMP production was only marginally suppressed. The values of patients with postmenopausal osteoporosis were in the range of those of earlier studied patients with Paget's disease and clinical resistance to sCT. There was a linear relation between the antibody dilution-50 and the serum dilution required for half-maximal inhibition of cAMP production (P less than 0.01). In conclusion, neutralizing antibodies to sCT may contribute to the decreased responsiveness of bone mineral loss during prolonged treatment with sCT.