Investigation of the role of endosomal Toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sj?gren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings.     

Current treatment of hepatitis C-associated rheumatic diseases

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient''s conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren''s syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient''s evaluation, including hepatic, virological, and immunological findings.     

Coexistence of growth hormone deficiency and autoimmune polyglandular syndrome type 3

Both adult-onset growth hormone deficiency and autoimmune polyglandular syndrome are more frequent clinical entities than previously thought. In light of research carried out in recent years, it seems that growth hormone deficiency may be associated with proinflammatory state. This study describes a unique case of adult-onset growth hormone deficiency secondary to a traumatic brain injury in a young man, which was followed by the development of autoimmune polyglandular syndrome type 3. We discuss diagnostic and treatment dilemmas associated with discovering and management of both disorders in this patient. We conclude that in predisposed individuals growth hormone deficiency may lead to the development of autoimmune disorders of endocrine glands and/or exacerbate their clinical course.     

Role of non-immune mechanisms of muscle damage in idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune diseases that are characterized by symmetrical skeletal muscle weakness and muscle inflammation with no known cause. Like other autoimmune diseases, IIMs are treated with either glucocorticoids or immunosuppressive drugs. However, many patients with an IIM are frequently resistant to immunosuppressive treatments, and there is compelling evidence to indicate that not only adaptive immune but also several non-immune mechanisms play a role in the pathogenesis of these disorders. Here, we focus on some of the evidence related to pathologic mechanisms, such as the innate immune response, endoplasmic reticulum stress, non-immune consequences of MHC class I overexpression, metabolic disturbances, and hypoxia. These mechanisms may explain how IIM-related pathologic processes can continue even in the face of immunosuppressive therapies. These data indicate that therapeutic strategies in IIMs should be directed at both immune and non-immune mechanisms of muscle damage.     

A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune diseases that are characterized by symmetrical skeletal muscle weakness and muscle inflammation with no known cause. Like other autoimmune diseases, IIMs are treated with either glucocorticoids or immunosuppressive drugs. However, many patients with an IIM are frequently resistant to immunosuppressive treatments, and there is compelling evidence to indicate that not only adaptive immune but also several non-immune mechanisms play a role in the pathogenesis of these disorders. Here, we focus on some of the evidence related to pathologic mechanisms, such as the innate immune response, endoplasmic reticulum stress, non-immune consequences of MHC class I overexpression, metabolic disturbances, and hypoxia. These mechanisms may explain how IIM-related pathologic processes can continue even in the face of immunosuppressive therapies. These data indicate that therapeutic strategies in IIMs should be directed at both immune and non-immune mechanisms of muscle damage.     

Nonischemic Cardiomyopathy Associated with Autoimmune Polyglandular Syndrome Type II

ObjectiveTo report a case of nonischemic cardiomyopathy associated with autoimmune polyglandular syndrome type II (APS-II).MethodsWe describe our patient’s clinical features, evaluation, and outcome. In addition, a literature review of cardiomyopathy associated with polyendocrinopathy syndromes is presented.ResultsThe component disorders of APS-II are Addison’s disease in combination with either autoimmune thyroid disease or type 1 (insulin-dependent) diabetes. Although numerous other autoimmune conditions have been reported in conjunction with APS-II, cardiomyopathy has not been previously described as part of this syndrome. The current patient was a 32-year-old man who, during a 5-year period, was diagnosed as having type 1 diabetes mellitus, Crohn’s disease, and Addison’s disease. In 2001, he presented with severe heart failure that progressed rapidly and eventually necessitated cardiac transplantation.ConclusionAlthough autoimmune cardiomyopathy has been associated with other autoimmune disorders, to our knowledge this is the first reported case of cardiomyopathy in association with an autoimmune polyglandular syndrome. Patients with this syndrome should undergo clinical evaluation for heart failure. (Endocr Pract. 2007;13:59-62)     

Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection

In the light of the enthusiasm to use of recombinant human granulocyte colony-stimulating factor (G-CSF) for immunomodulation and neuroprotection, it should be remembered that the current knowledge is based on a century of laborious research. G-CSF is a pleiotropic cytokine playing a major role as regulator of haematopoiesis. Although the precise mechanisms of G-CSF are not known, there is growing evidence supporting the notion that G-CSF also exerts profound immunoregulatory effect in adaptive immunity and has a neuroprotective role in both cerebral ischemia and neurodegeneration. Here, we describe the immunomodulation and the neuroprotection that can be achieved with G-CSF, and summarize possible mechanisms of G-CSF as a potential therapeutic agent in autoimmune diseases and neurological disorders. Our understanding of these novel sites of action of G-CSF has opened therapeutic avenues for the treatment of autoimmune diseases and neurological disorders, and has translated the beneficial effects of G-CSF from basic experiments to clinical patients.     

Autoimmune channelopathies and related neurological disorders

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.     

Amplification of autoimmune disease by infection

Reports of infection with certain chronic persistent microbes (herpesviruses or Chlamydiae) in human autoimmune diseases are consistent with the hypothesis that these microbes are reactivated in the setting of immunodeficiency and often target the site of autoimmune inflammation. New experimental animal models demonstrate the principle. A herpesvirus or Chlamydia species can be used to infect mice with induced transient autoimmune diseases. This results in increased disease severity and even relapse. The evidence suggests that the organisms are specifically imported to the inflammatory sites and cause further tissue destruction, especially when the host is immunosuppressed. We review the evidence for the amplification of autoimmune inflammatory disease by microbial infection, which may be a general mechanism applicable to many human diseases. We suggest that patients with autoimmune disorders receiving immunosuppressing drugs should benefit from preventive antiviral therapy.     

Antinuclear antibodies defining autoimmunity pathways

Immunofluorescent imaging has been a powerful technique in helping to identify intracellular nuclear and cytoplasmic molecules which are target antigens of autoantibodies in systemic autoimmune disorders. Patterns of staining can be correlated with molecules engaged in specific cellular functions and distributed in distinct cellular domains. Different autoimmune disorders have different profiles of autoantibodies, and immunodiagnostics has become an important adjunct in differential diagnosis. An important finding that has eluded explanation is the presence of autoantibodies to many different antigens, manifested strikingly in systemic lupus erythematosus. In cancer, the occurrence of autoantibodies to tumor-associated antigens is not uncommon and a characteristic feature is also the presence of multiple autoantibodies. The targeted tumor-associated antigens are either oncogene or tumor suppressor gene products or their coactivators, which are altered or mutated and driving the autoimmune response. Most cancer cells have between two and eight mutated genes before oncogenic transformation occurs, initiating a process called synthetic lethality in tumorigenesis pathways. These observations beg the question of whether there are similar mechanisms in systemic lupus erythematosus and other disorders driving autoimmunity pathways. Targeting molecules that are synthetic lethal to each other is in the forefront of the search for anticancer therapy, and this could also be an objective in systemic autoimmune disorders.     

Diagnostic and prognostic biomarker discovery strategies for autoimmune disorders

Current clinical, laboratory or radiological parameters cannot accurately diagnose or predict disease outcomes in a range of autoimmune disorders. Biomarkers which can diagnose at an earlier time point, predict outcome or help guide therapeutic strategies in autoimmune diseases could improve clinical management of this broad group of debilitating disorders. Additionally, there is a growing need for a deeper understanding of multi-factorial autoimmune disorders.Proteomic platforms offering a multiplex approach are more likely to reflect the complexity of autoimmune disease processes. Findings from proteomic based studies of three distinct autoimmune diseases are presented and strategies compared. It is the authors' view that such approaches are likely to be fruitful in the movement of autoimmune disease treatment away from reactive decisions and towards a preventative stand point.     

Coeliac disease in endocrine diseases of autoimmune origin

Abstract Coeliac disease (CD, sometimes called gluten-sensitive enteropathy or nontropical sprue) is an inflammatory disorder of the small intestine of autoimmune origin. It occurs in genetically predisposed people and is induced by a gluten protein, which is a component of wheat. The prevalence of histologically confirmed CD is estimated in screening studies of adults in the United States and Europe to be between 0.2% and 1.0%. The results of previous studies have indicated that the prevalence of CD is increased in patients with other autoimmune disorders such as: autoimmune thyroid diseases, type 1 diabetes mellitus, and Addison's disease. A coincidence of the above diseases constitutes autoimmune polyglandular syndrome (APS). The high prevalence of CD in APS is probably due to the common genetic predisposition to the coexistent autoimmune diseases. The majority of adult patients have the atypical or silent type of the disease. This is the main reason why CD so often goes undiagnosed or the diagnosis is delayed. CD, if undiagnosed and untreated, is associated with many medical disorders including haematological (anaemia), metabolical (osteopenia/osteoporosis), obstetric-gynaecological (infertility, spontaneous abortions, late puberty, early menopause), neurological (migraine, ataxia, epilepsy) as well as with an increased risk of malignancy, especially: enteropathy-associated T-cell lymphoma, small intestine adenocarcinoma, and oesophageal and oropharyngeal carcinomas. Early introduction of a gluten-free diet and lifelong adherence to this treatment decreases the risk of these complications.     

Neural and Pavlovian influences on immunity

The traditional view that the nervous and immune systems are functionally independent (aside from general stress effects and autoimmune disorders of the nervous system) is being challenged by a new view that the nervous system regulates the activity of the immune system. If this is true, it should be possible to change the activity of the immune system by means of Pavlovian conditioning, just as it is possible to condition other physiological events influenced by the autonomic nervous system or neuroendocrine substances. Evidence for autonomic and neuroendocrine modulation of immune activity is briefly reviewed; and, the various studies reporting conditioned immune effects, the physiological mechanisms most likely involved, and their possible significance are discussed.     

Mixed cryoglobulinemia

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology characterized by injury of the intrahepatic bile ducts that may eventually lead to liver failure. Affected individuals are usually in their fifth to seventh decades of life at time of diagnosis, and 90% are women. Annual incidence is estimated between 0.7 and 49 cases per million-population and prevalence between 6.7 and 940 cases per million-population (depending on age and sex). The majority of patients are asymptomatic at diagnosis, however, some patients present with symptoms of fatigue and/or pruritus. Patients may even present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. PBC is associated with other autoimmune diseases such as Sjogren's syndrome, scleroderma, Raynaud's phenomenon and CREST syndrome and is regarded as an organ specific autoimmune disease. Genetic susceptibility as a predisposing factor for PBC has been suggested. Environmental factors may have potential causative role (infection, chemicals, smoking). Diagnosis is based on a combination of clinical features, abnormal liver biochemical pattern in a cholestatic picture persisting for more than six months and presence of detectable antimitochondrial antibodies (AMA) in serum. All AMA negative patients with cholestatic liver disease should be carefully evaluated with cholangiography and liver biopsy. Ursodeoxycholic acid (UDCA) is the only currently known medication that can slow the disease progression. Patients, particularly those who start UDCA treatment at early-stage disease and who respond in terms of improvement of the liver biochemistry, have a good prognosis. Liver transplantation is usually an option for patients with liver failure and the outcome is 70% survival at 7 years. Recently, animal models have been discovered that may provide a new insight into the pathogenesis of this disease and facilitate appreciation for novel treatment in PBC.     

Apoptosis in the effector phase of autoimmune diabetes, multiple sclerosis and thyroiditis

The immune system is unusual in two respects. It produces billions of new cells daily that traffic throughout the body and cells within the system proliferate rapidly following exposure to an infectious agent. Both of these attributes require that cell production be regulated by cell death. Human diseases characterized by accelerated cell death leading to immunodeficiency disorders or by reduced cell death leading to systemic autoimmune diseases have been identified. In certain autoimmune diseases, the immune system directs its powerful cytotoxic effector mechanisms against specialized cells such as oligodendrocytes in multiple sclerosis, the beta cells of the pancreas in diabetes mellitus and thyrocytes in Hashimoto's thyroiditis. In this review, we examine the cytotoxic effector pathways implicated in cell death in organ specific autoimmune disorders.     

Immune and autoimmune disorders in HCV chronic liver disease: personal experience and commentary on literature

HCV chronic liver disease can be associated with a plethora of immune and autoimmune perturbations and many authors claim that HCV chronic infection can play an important role in the pathogenesis of these disorders. To compare our experience with literature reports, we performed a retrospective study on the case histories of 265 patients with HCV chronic liver disease, evaluating the type and prevalence of the associated immune and autoimmune manifestations. We found that the patients with HCV chronic liver disease can present arthromyalgias (7.1% of the patients), Sj?rgen's syndrome (5.2%), thyroiditis (4.1%), rheumatoid arthritis (2.2%), autoimmune thrombocytopenia (2.6%), mixed cryoglobulinemia (1.5%), autoimmune anemia (0.3%) and oral lichen planus (0.3%). We claim that HCV liver infection is able to induce immune and autoimmune perturbations, without playing a significant role in the pathogenesis of a well-defined disorder.     

Methods of hair loss evaluation in patients with endocrine disorders

Hair loss may accompany several endocrine disorders, including hypopituitarism, hypothyreosis, hyperthyreosis, hypoparathyroidism, diabetes mellitus, growth hormone deficiency, hyperprolactinaemia, polycystic ovary syndrome, SAHA syndrome, congenital adrenal hyperplasia, Cushing syndrome, or virilising tumours. Most patients with endocrine disorders present with diffuse non-scarring alopecia, such as anagen effluvium, telogen effluvium or androgenetic alopecia. Focal non-scarring alopecia, such as alopecia areata coexisting with autoimmune thyroiditis, is less frequent and scarring alopecia is a rare finding in patients with endocrine abnormalities. In some cases an endocrine disorder may be suspected based on dermatological findings during hair loss evaluation. Classic methods of hair evaluation include hair weighing, pull test, wash test, the trichogram, and histopathological examination. Newly developed non-invasive diagnostic techniques include the phototrichogram, trichoscan, trichoscopy, and reflectance confocal microscopy.     

Abnormalities of B cell phenotype,immunoglobulin gene expression and the emergence of autoimmunity in Sjögren's syndrome

Primary Sj?gren's syndrome (pSS) is an autoimmune disorder characterized by specific pathologic features and the production of typical autoantibodies. In addition, characteristic changes in the distribution of peripheral B cell subsets and differences in use of immunoglobulin variable-region genes are also features of pSS. Comparison of B cells from the blood and parotid gland of patients with pSS with those of normal donors suggests that there is a depletion of memory B cells from the peripheral blood and an accumulation or retention of these antigen-experienced B cells in the parotids. Because disordered selection leads to considerable differences in the B cell repertoire in these patients, the delineation of its nature should provide important further clues to the pathogenesis of this autoimmune inflammatory disorder.     

Report of two Turkish infants with Norman-Roberts syndrome

Lissencephaly or agyria refers to a rare disorder that is characterized by the absence of cerebral convolutions and a poorly formed sylvian fissure, giving the appearance of a 3-4 months old fetal brain. At present more than 25 dysmorphology syndromes with lissencephaly or other disorders of neuronal migration have been described. In 1976, Norman et al. reported on two patients with lissencephaly type I and short, sloping forehead, an atypical phenotype for Miller-Dieker syndrome, a more common lissencephaly syndrome. In this article, we report two Turkish female infants whose abnormal findings were consistent with Norman-Roberts syndrome because of their very rare presentation. Both patients had typical cranio-facial abnormalities and abnormal magnetic resonance imaging findings, but no deletion in 17p13.3 for Miller-Dieker syndrome. In addition to the typical findings of Norman-Roberts syndrome, case 1 had atrial septal defect, corpus callosum agenesis, intracranial widespread calcification and case 2 had bilateral macular cherry-red spot, persistent foramen ovale, increased blood level of C6 hexanoylcarnitine, cavum septum pellucidum vergae anomaly and cerebellar atrophy. In conclusion, we would like to emphasize that Norman-Roberts syndrome should also be considered in infants with lissencephaly. A detailed physical examination, chromosomal and fluorescence in situ hybridization (FISH) analysis to exclude a deletion in 17p13.3 should be performed for the definite diagnosis of the syndrome.     

Cause of pain in patients surgically treated for cholelithiasis and post-cholecystectomy syndrome]

Cholecystectomy does not mean an end of all problems in every patients because some of operated patients continue to complain. Usually such complaints are called post-cholecystectomy syndrome. Eighty three patients, who underwent cholecystectomy were examined. Postoperative complications were excluded, and post-cholecystectomy syndrome diagnosed because of persisting complaints. Definite additional disease associated with gastric and duodenal disorders was found in about 50% of all examined patients (56 cases). In further 23 patients repeated diagnostic tests enabled to establish probable reason of the disorders. The studies have shown that disorders noted after cholecystectomy and termed as post-cholecystectomy syndrome are as much as in 63% of patients not related to previous surgery. Therefore, this widely used name should not be applied to all complaints following cholecystectomy, and attempts of finding other causes of the ailments including other organs diseases should be undertaken.