Selected Aspects in the Pathogenesis of Autoimmune Diseases.

Autoimmune processes can be found in physiological circumstances. However, they are quenched with properly functioning regulatory mechanisms and do not evolve into full-blown autoimmune diseases. Once developed, autoimmune diseases are characterized by signature clinical features, accompanied by sustained cellular and/or humoral immunological abnormalities. Genetic, environmental, and hormonal defects, as well as a quantitative and qualitative impairment of immunoregulatory functions, have been shown in parallel to the relative dominance of proinflammatory Th17 cells in many of these diseases. In this review we focus on the derailed balance between regulatory and Th17 cells in the pathogenesis of autoimmune diseases. Additionally, we depict a cytokine imbalance, which gives rise to a biased T-cell homeostasis. The assessment of Th17/Treg-cell ratio and the simultaneous quantitation of cytokines, may give a useful diagnostic tool in autoimmune diseases. We also depict the multifaceted role of dendritic cells, serving as antigen presenting cells, contributing to the development of the pathognomonic cytokine signature and promote cellular and humoral autoimmune responses. Finally we describe the function and role of extracellular vesicles in particular autoimmune diseases. Targeting these key players of disease progression in patients with autoimmune diseases by immunomodulating therapy may be beneficial in future therapeutic strategies.

Lifestyle and other related factors for the development of mixed connective tissue disease among Japanese females in comparison with systemic lupus erythematosus.

OBJECTIVE: The etiology of mixed connective tissue disease (MCTD) has not been elucidated in detail. Case control studies of MCTD and systemic lupus erythematosus (SLE) were conducted in order to compare factors related to these two diseases. METHODS: We selected 48 MCTD and 54 SLE female patients throughout Japan from 2009 to 2010. Controls were 182 female patients who visited the clinics of general internal medicine during the study periods. RESULTS: Smoking and walking a longer time showed an increased age-adjusted risk for MCTD as well as SLE. On the other hand, frequent intake of bread increased the risk of MCTD and high intake of green tea decreased the risk of MCTD. Even after an additional adjustment of smoking and drinking, frequent intake of bread increased the risk of MCTD, while walking increased the risk of SLE. CONCLUSION: The present study suggests that Westernization of dietary habits (i.e. frequent intake of bread and low intake of green tea) may increase the risk of MCTD, while walking may increase the risk of SLE (probably due to exposure to the sunlight) among Japanese females. Further studies are needed to confirm the result of the present study.

"Mixed connective tissue disease": a condition in search of an identity.

Mixed connective tissue disease was first described as a new autoimmune rheumatic disease in 1972 based on the claim of a distinct clinical picture associated with anti-RNP antibody positivity. Subsequently, this new entity has divided opinions in the rheumatology community. We have reviewed recent cohort studies with more than 100 patients, comparing the clinical and immunological features, treatment, prognosis and evolution to well-defined autoimmune rheumatic diseases. We also reviewed clinical features of undifferentiated autoimmune rheumatic diseases based on the most recent studies. After gathering and reviewing these data, we discuss whether the designation "mixed connective tissue disease" should be maintained.

Phosphaturic mesenchymal tumor and related wound problem.

INTRODUCTION: Phosphaturic mesenchymal tumor mixed connective tissue type (PMT/MCT) is the most common type (up to 90%) of phosphaturic mesenchymal tumor (PMT), a rare clinicopathologic entity. Besides overproduction of fibroblast growth factor 23 (FGF23), there is a big variation of immunohistochemical characteristic across types of PMT, which makes it difficult to obtain an early diagnosis of PMT/MCT. As a benign tumor, PMT/MCT usually happens in subcutaneous tissues and leads to nonhealing of wound. A complete excision of PMT/MCT facilitates wound healing. CONCLUSIONS: Review of the existing evidence indicates that early diagnosis of PMT/MCT is critically important when treating PMT/MCT wound. Hence standardization of early diagnosis for PMT/MCT is mandated.

Does mixed connective tissue disease exist? Yes.

For patients who have combined features of rheumatoid arthritis, the limited cutaneous form of systemic sclerosis, and inflammatory myopathies, the concept of mixed connective tissue disease (MCTD) often helps to predict and diagnose organ problems and to educate the patient accordingly. With high titer IgG antibodies to U1 ribonucleoprotein (U1-snRNP), this concept is supported by a specific serologic marker, and autoantibodies to U1-snRNP and to heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 display MCTD specificity with regard to the recognized epitopes. In addition, the association of MCTD with HLA-DR4 distinguishes it from systemic erythematosus lupus and systemic sclerosis, and speaks to its being a disease entity, rather than a mixture of yet undifferentiated collagen vascular diseases. The authors believe that the concept is useful in daily practice and accurate in the idea that MCTD constitutes a disease entity of its own.

Mixed connective tissue disease: still crazy after all these years.

Mixed connective tissue disease (MCTD) remains a controversial diagnosis. The classification criteria have changed significantly from the original description by Sharp and colleagues in 1972 after follow-up of the original and other MCTD patients. In this article we review the clinical, serologic, and genetic studies of MCTD published in the last 10 years and ask if this term is appropriate.

Pediatric-onset mixed connective tissue disease.

This article discusses the literature on pediatric-onset mixed connective tissue disease (MCTD) and adds 34 new cases. Although not benign, pediatric-onset MCTD carries less mortality than adult-onset disease.

Pregnancy in mixed connective tissue disease.

This article discusses fetal and maternal morbidity in women who have mixed connective tissue disease.

Melkersson-Rosenthal syndrome as an early manifestation of mixed connective tissue disease.

PURPOSE OF REVIEW: We aim to illustrate the potential viability of MCTD as an underlying aetiology of Melkersson-Rosenthal syndrome. The case is probably the first description available in the literature of the Melkersson-Rosenthal as an early manifestation of mixed connective tissue disease. RECENT FINDINGS: The Melkersson-Rosenthal syndrome consists of a triad of recurrent lip and/or face swelling, fissured tongue, and intermittent facial palsy. Mixed connective tissue disease is a multisystemic disorder with overlapping features of systemic lupus erythematosus, scleroderma, and polymyositis, and is differentiated from them by a high titer of antibodies to ribonucleoprotein. The paper presents a case report of Melkersson-Rosenthal syndrome with an onset in childhood that derived from vasculitis that turned out to be an early manifestation of mixed connective tissue disease. We used MRI to evaluate patient's brain structure and Immunoblot Ena Profil 1 test to test serum autoantibodies level. The patient has a typical for Melkersson-Rosenthal syndrome triad of symptoms: bilateral facial nerve palsy, lingua plicata and facial oedema. Both TC and MRI of the head show no changes as well as laboratory tests except Anti-SS-A (Anti-Ro) and Anti-RNP autoantibody serum level that was highly positive. Neurological involvement of the MCTD usually includes, according to the frequency of the occurrence, trigeminal neuralgia, headaches, sensorineural hearing, cerebral haemorrhage, transverse myelitis, cauda equina syndrome, retinal vasculitis, progressive multifocal encephalopathy, and demyelinating neuropathy. For clinical practice it is important to remember that Melkersson-Rosenthal syndrome can also be the neurological manifestation of MCTD, especially when accompanied by other systemic symptoms.

Isolated trigeminal sensory neuropathy: early manifestation of mixed connective tissue disease.

A young woman with mixed connective tissue disease (MCTD) had an isolated trigeminal sensory neuropathy as an early manifestation of the disease. Raynaud phenomenon occurred almost synchronously with the onset of trigeminal neuropathy and was followed by myositis, diffuse hand swelling, synovitis, and increased ribonucleoprotein antibody. Mixed connective tissue disease has overlapping features of systemic lupus erythematosus, scleroderma, and polymyositis, and is differentiated from them by high-titer antibody to ribonucleoprotein.

Connective tissue and joint disease in diabetes mellitus.

Connective tissue is ubiquitous and subject to alterations that result in changes in the extracellular matrix of vessels and tissues leading to the long-term complications of diabetes. This article reviews only those abnormalities of interstitial connective tissue involving skeleton, joints, skin, and periarticular tissues. Abnormalities in the skin and periarticular tissues result in syndromes limiting joint movement, including limited joint mobility, Dupuytren disease, flexor tenosynovitis, carpal tunnel syndrome, stiff-hand syndrome, and shoulder-hand reflex dystrophy. Of these, only limited joint mobility and stiff-hand syndrome occur exclusively in patients with diabetes. In all of these conditions, advanced glycation end products are thought to form as a result of nonenzymatic reaction of glucose with proteins, causing stiffening.

Analysis of T cell receptors specific for U1-70kD small nuclear ribonucleoprotein autoantigen: the alpha chain complementarity determining region three is highly conserved among connective tissue disease patients.

The U1-70kD autoantigen is a major target of B cell responses in patients with connective tissue diseases (CTD). T cell responses are important in the pathogenesis of CTD, however little is known about autoantigen-specific T cells in these diseases. We have recently proven that U1-70kD-reactive human T cells exist. To further characterize these autoreactive T cells, U1-70kD-reactive T cell clones have been generated from patients with CTD using either a recombinant fusion protein or synthetic peptides spanning the U1-70kD polypeptide. T cell receptors (TCR) isolated from the U1-70kD-reactive T cell clones were sequenced and the third complementarity-determining region (CDR3) compared to determine if a common motif was present. mAb blocking of antigen-induced proliferation was done to determine the HLA restriction element used in recognition of the U1-70kD autoantigen by T cells. The results presented here indicate that TCRAV CDR3 usage is highly restricted among U1-70kD autoantigen-specific human T cells clones derived from CTD patients with distinctive structural features. Furthermore, the recognition of the U1-70kD autoantigen occurs in the context of HLA-DR.

Autoimmune disease and silicone breast implants.

An association between crystalline silica and immune disease has long been recognized. However, despite ongoing case reports of systemic autoimmune disease in silicone implant recipients, the available data has not been sufficient to prove or disprove a causal relationship. Silicone has been shown to "bleed" from the implants and can migrate to distant sites. There is evidence of cellular and humoral immune responses to silicone in vivo, but the role of these responses in the development of connective tissue disorders has not been determined. Further studies are necessary to elucidate the role of silicone, if any, in the pathogenesis of autoimmune connective tissue disease. Meanwhile, the implant population needs to be closely monitored; their clinical management should be based on a case by case evaluation.

Mixed connective tissue disease and Sjögren's syndrome, accompanied by HTLV-I infection.

A 48-year-old Japanese woman with mixed connective tissue disease (MCTD) and Sjögren's syndrome (SjS) was a carrier of HTLV-I and had anti-HTLV-I antibodies in her serum. Moreover, her peripheral blood lymphocytes contained proviral DNA for the pX region of HTLV-I as detected by the polymerase chain reaction. An immunohistological study was performed on her minor salivary gland to detect gene products of HTLV-I (P19 and P28 proteins); specific staining was demonstrated only in the epithelium of the salivary ducts. HTLV-I and its associated immune dysfunction may be responsible for MCTD and SjS in this patient.

[Late reactions following implantation of silicone prostheses]. / Spätreaktionen nach Implantation von Silikonprothesen.

Silicone implants can provoke local reactions (granulomas, lymphadenopathy) and also systemic side-effects. About 80 case reports in the literature describe autoimmune disease following silicone augmentation. The clinical spectrum includes signs and symptoms of progressive sclerosis, mixed connective tissue disease and lupus erythematosus. We present 4 cases with possible autoimmune phenomena related to breast augmentation. After explantation in 1 case the clinical and immunological features disappeared, and the antinuclear antibodies subsequently decreased from a titre of 1:1280 (speckled form) to 1:160 (homogeneous form). To our knowledge there are no similar reports on systemic complications following the use of silicone in urology.

The spectrum of lung involvement in collagen vascular-like diseases following allogeneic hematopoietic stem cell transplantation: report of 6 cases and review of the literature.

Multisystem autoimmune diseases occurring after allogeneic hematopoietic stem cell transplantation are infrequent, late-onset manifestations that resemble well-defined collagen vascular disorders. Because the lung is frequently involved in the course of connective tissue disorders, we focused on lung manifestations occurring in autoimmune diseases following allogeneic stem cell transplantation. In the present series, we report 6 patients with systemic lupus erythematous, mixed connective tissue disease, Sjögren syndrome, polymyositis, and ANCA-positive vasculitis who presented with a spectrum of pulmonary manifestations affecting the airways, lung parenchyma, and probably respiratory muscles. We identified 3 different histopathologic patterns of interstitial pneumonia consistent with the underlying autoimmune disorder: lymphocytic interstitial pneumonia and non-specific interstitial pneumonia in 2 patients with Sjögren syndrome and diffuse alveolar damage in 1 patient with ANCA-positive vasculitis. These lung manifestations had poor prognoses. Further studies are needed to determine the optimal therapy for these complications.