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49-531: Anti-SSA/Ro autoantibodies are classified as extractable nuclear antigens . The Anti-SSA/Ro autoantibody targets Ro proteins, namely Ro52 and Ro60. Ro52 and Ro60 were originally thought to be one protein, however current findings show that they are two functionally distinct proteins encoded by genes on separate chromosomes. Anti-SSA/Ro autoantibodies are used in clinical settings as a diagnostic tool to identify patients with SLE and Sjögren's syndrome. In clinical tests for autoimmune disease, Anti-Ro antibodies are some of

98-521: A drug cause is suspected, that drug should be discontinued. Oxygen therapy at home is recommended in those with significantly low oxygen levels. Oxygen therapy in ILD is associated with improvements in quality of life but reductions in mortality are uncertain. Long-term oxygen therapy can be beneficial to people with ILD and hypoxemia to enhance gas exchange, lessen dyspnea, and increase physical activity. Pulmonary rehabilitation appears to be useful with

147-738: A prostaglandin I2 analogue) is indicated in the treatment of pulmonary hypertension secondary to interstitial lung disease and is associated with improved exercise capacity as measured by a 6-minute walk test. Those with ILD should stop smoking cigarettes if they smoke. Vaccinations against pneumococcus , Covid-19 , RSV and influenza are indicated in all those with ILD. Short acting opiates are known to improve breathlessness symptoms in those with end stage lung disease. The opiate agonist-antagonist nalbuphine and morphine are also known to improve coughing in those with ILD and other end stage lung diseases. The median survival in idiopathic pulmonary fibrosis

196-493: A restrictive pattern . Restrictive defects are defined by decreased TLC (total lung capacity), RV (residual volume), FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second). As both FVC and FEV1 are reduced, the FVC to FEV1 ratio remains normal or is increased. As disease progression increases and the lungs become stiffer lung volumes will continue to decrease; lower TLC, RV, FVC and FEV1 scores are associated with

245-419: A benefit in scleroderma associated ILD by helping to preserve lung function (as measured by FVC) at 48 weeks. The immunomodulators cyclophosphamide , mycophenolate mofetil and rituximab all showed improved lung function (as measured by % predicted FVC) compared to placebo in systemic sclerosis or scleroderma associated ILD. The inhaled vasodilator treprostinil (a synthetic prostacyclin which acts as

294-492: A camera is introduced into the airways followed by rapid freezing of an area of lung tissue prior to biopsy is associated a lower complication rate and a much lower mortality rate compared to VATS or surgical biopsy with near comparable diagnostic accuracy. There are four types of histopathologic patterns seen in ILD: usual interstitial pneumonia, non-specific interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage. There

343-645: A combination of both of these techniques to improve efficiency without sacrificing specificity. The current recommendation by European Consensus workshops is to screen for positive anti-ENAs with the ELISA technique. A more specific test such as CIEP will follow with samples that are identified as positive. The six main antigens used in immunological laboratories for detection are Ro , La , Sm , RNP , Scl-70 and Jo1 , which are screened for by Ouchterlony double immuno diffusion techniques and confirmed by immunoblotting . On anti-nuclear antibody tests, these antigens have

392-458: A disease if the levels of these autoantibodies increase or decrease. To confirm the presence of anti-ENAs, it is currently recommended to use two or more methods to confirm anti-ENAs to avoid false positives. The diagnosis of autoimmune connective tissue diseases (CTDs) is done through analysis of clinical symptoms and signs, but also through the identification of the autoantibodies directed against nuclear antigens. A 2002 paper also seeks to compare

441-665: A high-spatial-frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized. Radiologic appearance alone, however, is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process. Interstitial lung diseases can be classified according to radiologic patterns. For some types of paediatric ILDs and few forms adult ILDs, genetic causes have been identified. These may be identified by blood tests. For

490-408: A limited number of cases, this is a definite advantage, as a precise molecular diagnosis can be done; frequently then there is no need for a lung biopsy. Testing is available for ILD is not a single disease but encompasses many different pathological processes, hence treatment is different for each disease. If a specific occupational exposure cause is found, the person should avoid that environment. If

539-405: A lung biopsy as part of the diagnostic evaluation. A lung biopsy may be required if the clinical history and imaging are not clearly suggestive of a specific diagnosis or malignancy cannot otherwise be ruled out. Surgical lung biopsy or via a video-assisted thoracoscopic surgery (VATS) biopsy is associated with a mortality rate up to 1-2%. A bronchoscopic transbronchial cryobiopsy, in which

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588-417: A major disadvantage in that antibodies targeted against conformational epitopes can not be detected. On top of that, false positive can occur and the disease specificity is lower than other techniques. While each technique has their advantages and disadvantages, ELISA has the least severe disadvantages of potential for false positives (which are less dangerous than false negatives) and expensive. Many labs use

637-574: A median survival of 2.5-3.5 years. Idiopathic pulmonary fibrosis is interstitial lung disease for which no obvious cause can be identified (idiopathic) and is associated with typical findings both radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing, and fibroblastic foci). In 2015, interstitial lung disease, together with pulmonary sarcoidosis , affected 1.9 million people. They resulted in 122,000 deaths. ILD may be classified as to whether its cause

686-528: A more severe disease progression and poorer prognosis. Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early in the disease process. High-resolution CT of the chest is the preferred modality and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained at 10 mm intervals; high resolution CT examines 1–1.5 mm slices at 10 mm intervals using

735-487: A much lower disease specificity than alternative techniques. This is due to the inability to properly isolate the ENAs without large costs due to their association with complexes in the nucleus of the cell. Another worry with the ELISA technique is that anti-Sm antibodies have been reported in patients without SLE which would lead to over-investigating, but could be due to the quality of the antigen source used. Western blotting has

784-441: A positive ANA test alone does not suffice for diagnosis. In fact, low levels of ANAs can be found in healthy patients. The applications of anti-ENA testing varies from excluding patient groups from specific groups, connective tissue diseases, and to monitor disease activity. In essence, it allows clinicians to exclude specific autoimmune disorders if a particular autoantibody is not present, and allows clinicians to track progression of

833-448: A speckled pattern. ENAs originally referred to proteins found in a saline extract of cell nuclei . Components have since been more clearly identified and in fact include many cytoplasmic molecules. The misnomer, however, has remained. These proteins are intimately associated with various RNA molecules and are thus called ribonucleoproteins , but the nomenclature used for them is often a source of confusion, Sm, Ro and La were named after

882-415: A subcategory of lupus erythematosus, elevated levels of Ro52 are found regardless of expression of Anti-Ro autoantibodies. The presence of Anti-SSA/Ro in pregnant women with SLE is associated with an increased risk of neonatal lupus erythematosus which can be accompanied by congenital heart block (CHB) in the fetus. SLE-related symptoms in infants that arise from Anti-Ro/SSA resolve in about six months as

931-425: A type of small nuclear ribonucleoprotein (snRNPS). The location in the nucleus and association with spliceosomes or nucleosomes results in these ENAs being associated with additional RNA and proteins such as polymerases. This quality of ENAs often makes it difficult to purify and quantify their presence for clinical use. An extractable nuclear antigen panel , or an ENA panel, tests for presence of autoantibodies in

980-553: Is a cytosolic Fc receptor. Ro52 is a regulatory protein, and negatively moderates inflammatory response, such as the secretion of pro-inflammatory cytokines in the interleukin and INF families. Ro52 can both regulate and be induced by INF cytokines. Loss of function or blockage of Ro52 results in uncontrolled inflammation at the onset of injury or disease. Patients with SLE and SS not only show elevated levels of Anti-Ro antibodies, but also elevated levels of Ro52. Ro52 has one primary epitope to which anti-Ro/SSA binds, independent of

1029-481: Is derived from the ability to remove the autoantibodies from the nuclei with saline and common proteins. The method of identifying these specimens is why they are also referred to as antibodies to saline-extracted antigens. Anti-ENA is a grouping of antibodies often used to screen for mixed connective tissue disease (MCTD), Sjögren's syndrome and systemic lupus erythematosus and commonly is composed of six tests: Sensitivity and specificity of these tests depends on

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1078-969: Is economically feasible and specific to confirm a diagnosis. There are two sensitivities to note when viewing data from these gel-based techniques, assay sensitivity and disease sensitivity. Assay sensitivity is the ability to recognize when an antibody is present, while disease sensitivity is the ability to recognize the frequency in which the antibody occurs in a disease. Due to limitations of gel-based techniques in disease sensitivity, other techniques have been explored in order to increase assay sensitivity without decreasing disease sensitivity. For example, in patients with Systemic lupus erythematous (SLE), only 8–40% have detectable anti-SM when using gel-based assays. CIEP has been shown to be more sensitive than DID. Three additional techniques, passive hemagglutination, enzyme linked immunosorbent assay (ELISA), and western blotting (WB), can be used in order to identify ENAs and link them to specific diseases. Passive hemagglutination

1127-509: Is indicated for all people with ILD and the FVC loss and DLCO is prognostic, with an FVC loss of greater than 5% per year associated with a poor prognosis in fibrosis subtypes of ILD. A chest x-ray is 63% sensitive and 93% specific for ILD. With advances in computed tomography , CT scans of the chest have supplanted lung biopsy as the preferred diagnostic test for ILD. A thoracic CT scan is 91% sensitive and 71% specific for ILD. In higher income countries, less than 10% of people with ILD undergo

1176-580: Is not known (idiopathic) or known (secondary). Idiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). They were subclassified by the American Thoracic Society in 2002 into 7 subgroups: Secondary ILDs are those diseases with a known etiology, including: Connective tissue related disease represents approximately 25% of all cases of ILD. Diagnosis of ILD involves assessing

1225-520: Is not part of the TRIM family. Ro60 is encoded by a gene 32 kb in length and acts to regulate the fate of misfolded RNA within the host cell. Ro60 forms a ribonucleoprotein complex with one molecule of noncoding Y1, Y3, Y4, or Y5RNA, all of which are approximately 100 nucleotides in length, to form the epitope that Anti-Ro60 recognizes. The absence of Ro60 results in an elevated immune response and decreased resilience to immune-related stress. The epitope of

1274-436: Is significant overlap of the histopathological and radiologic features of each ILD type making diagnosis challenging; even with lung biopsy, 15% of cases of ILD cannot be classified. Most patients with suspected ILD are likely to undergo complete pulmonary function testing . These tests are useful in diagnosis and determining severity of the disease. Although there is large diversity in interstitial lung disease, most follow

1323-477: Is used to distinguish these diseases from obstructive airways diseases . There are specific types in children, known as children's interstitial lung diseases . The acronym ChILD is sometimes used for this group of diseases. In children, the pathophysiology involves a genetic component, exposure-related injury, autoimmune dysregulation, or all of the components. Thirty to 40% of those with interstitial lung disease eventually develop pulmonary fibrosis which has

1372-416: The alveoli (air sacs) of the lungs . It concerns alveolar epithelium , pulmonary capillary endothelium , basement membrane , and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and

1421-468: The Ro antigen in autoimmune disorders remains unknown. The Ro52 gene is officially termed TRIM21 , as it is a member of the tripartite motif protein (TRIM) family, qualified by its RING and B-box domains. The protein is typically located in the cytoplasm, though it can move to the nucleus in the presence of pro-inflammatory signals, and it can also be expressed on the cell surface. There is evidence that Ro52 itself

1470-859: The Ro60 protein is similar to that of the Epstein-Barr virus, and the presence of the virus may enhance the autoimmune response to Ro60, as anti-Epstein Barr antibodies can target the protein. Anti-Ro/SSA antibodies are found in 40–90% of patients with systematic lupus erythematosus (SLE). The antibodies can be detected years before symptoms of SLE surface, making them an effective diagnostic tool. In patients with SLE, high levels of Anti-Ro/SSA are correlated with elevated levels of IFN-α. The presence of Anti-Ro/SSA antibodies also correlates with symptoms of photosensitivity , cutaneous vasculitis , and hematological disorders . In individuals with cutaneous lupus erythematosus (CLE),

1519-414: The antibodies are precipitin negative, lack antinuclear antibody (ANA) specific fluorescence staining patterns, and have a low signature in ELISA assays. Furthermore, Ro52 can be masked by Anti-Ro60 antibodies in lab tests that simultaneously assess the two antibodies. Anti-Ro/SSA can target Ro52 and Ro60 proteins. Most Anti-Ro/SSA activity occurs on the cell surface, wherein Ro proteins are expressed on

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1568-550: The antigen as Ro – named after the patient from which the antibodies were extracted, while Alspaugh & Tanand used the term SSA. It was later found that the labs described the same antigen, hence the compound term for the antibody, Anti-SSA/Ro, Anti-Ro/SSA. In laboratory settings, ELISA and immunodiffusion assays are most commonly used to detect levels of Anti-Ro/SSA antibodies in patient sera. Antibodies specific to Ro52 are difficult to detect via laboratory testing. Their low detectability may be attributed to several factors:

1617-888: The autoimmune disease. The most common domain anti-Ro52 targets is the coiled coil (cc) domain, as well as the RING and B-box domains. Ro52 does not bind to small cytoplasmic non-coding RNA strands (hY-RNA). The notion that Ro52 formed a complex with Y RNA resulted from studies that suggesting that Ro52 and Ro60 formed a complex together. Ro52 may impact the pathogenesis of autoimmune disease: patients with SLE and SS have been shown to express high levels of Ro52 transcripts. Though Ro52 and Ro60 are often seen in elevated levels together in patients with autoimmune disease, Ro52 manifests without Ro60 in SS. Additionally, Anti-Ro52 antibody has been identified at elevated levels in patients with interstitial lung disease , as well as in autoimmune hepatitis type 1. Ro60

1666-573: The benefits being sustainable longer term with improvements in exercise capacity (as measured by a six minute walking test), dyspnea , and quality of life. Lung transplantation is an option if the ILD progresses despite therapy in appropriately selected patients with no other contraindications. Life expectancy after lung transplant is 5.2 years in those with idiopathic interstitial pneumonias (including idiopathic pulmonary fibrosis) and 6.7 years in those with other types of ILD. The antifibrotics pirfenidone and nintedanib have been shown to slow

1715-465: The blood that react with proteins in the cell nucleus. It is usually done as a follow-up to a positive antinuclear antibody ( ANA ) test and when one is showing symptoms of an autoimmune disorder . The ANA tests for the presence or absence of autoantibodies, while the ENA panel evaluates which proteins in the cell nucleus the autoantibodies recognize. The ENA panel helps diagnosis, distinguish between, and monitor

1764-475: The cell membrane and extracellular Anti-Ro/SSAs bind to Ro. There is some evidence that the IgG isotype of anti-Ro/SSA antibody can enter the cell. The mechanism that induces Anti-Ro/SSA production in autoimmune disorders remains under study. Some proposed factors that may stimulate production are viral infection, treatment of cells with TNF-α , cellular apoptosis , and exposure to UV irradiation . Certain alleles of

1813-505: The decline in lung function (as measured by forced vital capacity [FVC]) in those with ILD compared to placebo. Pirfenidone was associated with a 45% less decline in FVC at 52 weeks compared to placebo in a trial involving people with idiopathic pulmonary fibrosis, and was associated with a slower FVC decline in those with progressive pulmonary fibrosis. Nintedanib was also associated with a slower FVC decline and increased mean survival in people with ILD. The immunomodulator tocilizumab has

1862-666: The diagnostic tests used in immunology laboratories to measure anti-ENAs and ways to improve this testing and reporting. Double immunodiffusion (DID) and counterimmunoelectrophoresis (CIEP), two forms of gel-based techniques , are used to gain information on the clinical significance and the role of these antibodies in those with CTDs. Since the discovery of ENAs, they have been used as a diagnostic tool in connective tissue disease. Two widely used gel-based techniques were used to identify anti-ENAs and their associations to disease in early work, double immunodiffusion (DID) and counterimmunoelectrophoresis (CIEP). Both of these techniques require

1911-400: The first 2 letters of the surnames of the patients in whom they were first found. Two proteins associated with Sjögren syndrome were independently described as antigens A and B, but are now known to be identical to Ro and La respectively, i.e. SS-A = Ro and SS-B = La. ENA (extractable nuclear antigen) panel tests, test for autoantibodies to proteins in the cell nucleus. The term "extractable"

1960-488: The human major histocompatibility complex ( MHC II , called HLA II in humans) have been associated with the presence of Anti-Ro antibodies and the spread of the immune response. Anti-Ro/SSA associates with the HLA II alleles HLA-DR3 and HLA-DR2 , as well as some HLA-DQ alleles. The T-cell response plays a role in the formation of Anti-Ro/SSA antibodies due to T-cell affinity for MHC class II. The specific pathogenic role of

2009-404: The most consistently and frequently detected among autoantibodies. Anti-Ro autoantibodies are often found in conjunction with a similar antibody, Anti-La/SSB (also called anti–SS-B or anti–SS-B/La), in patients with SS. These two antibodies share pathological characteristics. In 1969, two separate labs simultaneously identified antigens in the sera of SLE and SS patients. Clark et al. referred to

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2058-776: The mother's antibodies leave the baby's system. Mothers of babies with NLE most often do not show signs of autoimmune disease. The role of Anti-SSA/Ro in NLE is remains under study, as recent studies have suggested that CHB in neonates is more generally linked to instances of autoimmunity in the mother rather than the presence of Anti-Ro/SSA antibody. Extractable nuclear antigen Extractable nuclear antigens ( ENAs ) are over 100 different soluble cytoplasmic and nuclear antigens . They are known as "extractable" because they can be removed from cell nuclei using saline and represent six main proteins: Ro, La, Sm, RNP, Scl-70, Jo1. Most ENAs are part of spliceosomes or nucleosomes complexes and are

2107-560: The precipitation of antigens for valid results. Depending on the anti-ENA being investigated, one technique may be used over the other. For example, Scl-70 antigen is less negatively charged, which can result in the antigen traveling in the same direction as the antibody. This would result in the antibody-antigen complex not precipitating; leading to invalid results. In addition, some anti-SS-B antibodies commonly identified in Sjögren syndrome may not be detected with this method. However, this method

2156-495: The progression of autoimmune diseases and is performed with a simple blood draw. While the levels of autoantibodies may fluctuate through one's life, once one develops autoantibodies, one will always have them. Autoantibodies to these antigens are associated with particular connective tissue disorders. Indeed, in 84.3% of positive anti-ENA samples, ANA reagents were also found. The use of anti-ENA autoantibody tests can serve as additional verification of an autoimmune disorder, because

2205-542: The signs and symptoms as well as a detailed history investigating occupational exposures. ILD usually presents with dyspnea, worsening exercise intolerance and 30-50% of those with ILD have a chronic cough. On examination, velcro crackles, in which the crackles compare to the sound of velcro being unfastened, are common in ILD. Pulmonary function tests usually show a restrictive defect with decreased diffusion capacity of carbon monoxide ( DLCO ) indicating reduced alveolar to blood capillary transport. Pulmonary function testing

2254-426: The tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD

2303-479: The type of assay employed, and will therefore vary by lab. The following table illustrates the sensitivity and specificity of ENA antibodies at detecting SLE with the ELISA technique. In addition, the use of ENA testing has also been used for the study of wheat related disorders such as celiac disease . A study conducted in 2018 screened patients with wheat related disorders for 10 anti-ENA antibodies. 73% of celiac disease subjects tested positive for anti-histone and

2352-441: Was popular in the late 1970s, but very few studies have been done using them and was restricted to anti-Sm and anti-ribonuclear protein (RNP) antibodies. Enzyme linked immunosorbent assay (ELISA) has become the most widely used technique for testing for anti-ENAs due to them being simple to perform, quantitative, and high volume output. While this method has increased assay sensitivity and is efficient for high volume labs, they have

2401-417: Was the most prevalent, which is typically associated with drug-induced lupus erythematosus . This implicates a high probability of an autoimmune disorder in patients with wheat-related disorders. Interstitial lung disease Interstitial lung disease ( ILD ), or diffuse parenchymal lung disease ( DPLD ), is a group of respiratory diseases affecting the interstitium (the tissue) and space around

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