Detection and diagnostic utility of paraproteins in body fluids

体液中副蛋白的检​​测和诊断用途

• 批准号: 7593143
• 负责人: Gyorgy Csako
• 金额: $ 3.9万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593143
• 关键词: Age; Benign; Benign Monoclonal Gammopathies; Biological Assay; Body Fluids; Case-Control Studies; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Data; Clinical Research; Confidence Intervals; Connective Tissue Diseases; Detection; Development; Diagnosis; Diagnostic; Disease; Electrophoresis; Evaluation; Familial Waldenstrom' s macroglobulinaemia; Family; Follow-Up Studies; Frequencies; Future; Gamma globulin; Globulins; Glycine decarboxylase; Goals; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Implant; Internal Breast Prosthesis; Investigation; Laboratories; Light-Chain Immunoglobulins; Literature; Lymphoproliferative Disorders; Malignant - descriptor; Mass Spectrum Analysis; Monitor; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Odds Ratio; Paraproteinemias; Paraproteins; Patient Care; Patients; Pattern; Performance; Plasma Cells; Population; Predisposition; Prevention strategy; Process; Proteins; Relative (related person); Risk; Sepharose; Serum; Serum Globulins; Serum Proteins; Silicones; Study of serum; Techniques; Test Result; Urine; Validation; Waldenstrom Macroglobulinemia; Woman; base; clinically significant; cohort; follow-up; gammopathy; multiple myeloma M Protein; polyacrylamide gels; tertiary care

Study of immunoglobulins in various body fluids, especially in serum, urine and cerebrospinal fluid (CSF), is important for understanding the pathomechanism of a variety of diseases and for diagnosing and monitoring diseases. Protein electrophoresis (PEP) and immunofixation electrophoresis (IFE) are key techniques to identifiy protein abnormalities and to detect abnormal immunoglobulins (paraproteins) in body fluids. The paraproteins are the products of clonal or oligoclonal proliferation of plasma cells and, as such, may represent full immunoglobulins, free heavy chains, and/or free light chains of immunoglobulins. Correct identification of paraproteins can be hampered, however, by the occurrence of pseudoparaproteins (P-proteins). P-proteins are normally occurring proteins that mimic M-proteins in protein electrophoretic patterns. Over the past few months, we have observed several cases of urine P-proteins that had not been described in the existing literature. Using a combination of various analytical techniques (e.g., electrophoresis in agarose and polyacrylamide gel, immunoelectrophoresis, and mass spectrometry), we are now in the process to fully identify these P-proteins. In a collaborative study, we investigated possible associations between silicone breast implants and the occurrence of serum paraproteins as indicators of benign or malignant lymphoproliferative disorders, and, in particular, benign monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Prior studies have suggested abnormalities of serum proteins, including paraproteins, in women with silicone implants but did not control for the presence of connective-tissue disease (CTD). In our retrospective case-control study, performed in tertiary-care academic centers, we assessed possible alterations of serum proteins, including paraproteins, in such a population. Seventy-four women with silicone implants who subsequently developed CTD and 74 age- and CTD-matched women without silicone implants were assessed in the primary study; other groups were used for additional comparisons. Routine serum protein determinations and high-sensitivity protein electrophoresis and immunofixation electrophoresis were performed for detection of paraproteins. Women with silicone implants, either with or without CTD, had significantly lower serum total protein and alpha-1, alpha-2, beta, and gamma globulins, and IgG levels compared to those without silicone implants. There was no significant difference, however, in the frequency of paraproteinemia between women with silicone implants and CTD (9.5%) and age- and CTD-matched women without silicone implants (5.4%) (odd ratio 1.82 95% confidence intervals 0.51 to 6.45). Paraprotein isotypes were similar in the two groups and the clinical characteristics of the 13 women with paraproteinemia were comparable to an independent population of 10 women with silicone breast implants, CTD and previously diagnosed monoclonal gammopathies. In summary, in this first comprehensive study of serum proteins in women with silicone implants and CTD we found no substantially increased risk of monoclonal gammopathy. Women with silicone implants, however, had unexpectedly low serum globulin and immunoglobulin levels, with or without the subsequent development of CTD. The causes and clinical implications of these findings require further investigation. In another collaborative study, we investigated the clinical significance of immunoglobulin abnormalities in relatives of familial Waldenstrom macroglobulinemia (WM) patients in a follow-up study of three WM families originally evaluated 27 years previously. This study is the longest comprehensive follow-up of WM families to date. Based on the results of serum protein electrophoresis, immunofixation electrophoresis and clinical data, IgM monoclonal gammopathy seemed to be a phenotypic marker of WM susceptibility in some families and may carry a high risk of progression to WM. IgM polyclonal gammopathy may also be important in WM families. These observations require validation in larger studies and, if confirmed, may be used to identify a cohort (relatives with IgM monoclonal gammopathy) for future prevention strategies.

研究各种体液，特别是血清、尿液和脑脊液（CSF）中的免疫球蛋白，对于了解各种疾病的病理机制以及诊断和监测疾病具有重要意义。蛋白质电泳（PEP）和免疫固定电泳（IFE）是鉴定体液中蛋白质异常和检测异常免疫球蛋白（副蛋白）的关键技术。副蛋白是浆细胞的克隆或寡克隆增殖的产物，因此可以代表完整的免疫球蛋白、游离重链和/或免疫球蛋白的游离轻链。然而，副蛋白的正确鉴定可能会受到假副蛋白（P蛋白）的影响。P-蛋白是在蛋白质电泳模式中模拟M-蛋白的正常存在的蛋白质。在过去的几个月里，我们观察到几例尿P蛋白，这在现有的文献中没有描述。使用各种分析技术的组合（例如，琼脂糖和聚丙烯酰胺凝胶电泳，免疫电泳和质谱），我们现在正在充分鉴定这些P蛋白。 在一项合作研究中，我们研究了硅胶乳房植入体与血清副蛋白发生率之间的可能相关性，血清副蛋白作为良性或恶性淋巴组织增生性疾病的指标，特别是意义不明的良性单克隆丙种球蛋白病（MGUS）和多发性骨髓瘤（MM）。先前的研究表明，在植入硅胶的女性中，血清蛋白（包括副蛋白）异常，但未控制结缔组织病（CTD）的存在。在我们的回顾性病例对照研究中，在三级护理学术中心进行，我们评估了血清蛋白，包括副蛋白，在这样的人群中可能的改变。在主要研究中评估了74名随后发展为CTD的硅胶植入体女性和74名年龄和CTD匹配的无硅胶植入体女性;其他组用于额外的比较。采用常规血清蛋白测定、高灵敏度蛋白电泳和免疫固定电泳检测副蛋白。与没有硅胶植入体的女性相比，有或没有CTD的硅胶植入体女性的血清总蛋白和α-1，α-2，β和γ球蛋白以及IgG水平显著降低。然而，在植入硅胶植入体并患有CTD的女性（9.5%）与年龄和CTD匹配的未植入硅胶植入体的女性（5.4%）之间，副蛋白血症的发生率无显著差异（比值比1.82，95%置信区间0.51至6.45）。两组的副蛋白同种型相似，13名副蛋白血症女性的临床特征与10名患有硅胶乳房植入体、CTD和既往诊断的单克隆丙种球蛋白病的女性的独立人群相当。总之，在这项首次对硅胶植入体和CTD女性患者血清蛋白的综合研究中，我们发现单克隆丙种球蛋白病的风险没有显著增加。然而，植入硅胶的女性血清球蛋白和免疫球蛋白水平出乎意料地低，有或没有随后的CTD发展。这些发现的原因和临床意义需要进一步调查。 在另一项合作研究中，我们调查了家族性瓦尔登斯特伦巨球蛋白血症（WM）患者亲属中免疫球蛋白异常的临床意义，对27年前最初评估的三个WM家族进行了随访研究。这项研究是迄今为止对WM家族进行的时间最长的全面随访。根据血清蛋白电泳、免疫固定电泳和临床资料的结果，IgM单克隆丙种球蛋白病似乎是某些家系中WM易感性的表型标志，并可能具有进展为WM的高风险。IgM多克隆丙种球蛋白病也可能是重要的WM家庭。这些观察结果需要在更大规模的研究中进行验证，如果得到证实，可以用于确定未来预防策略的队列（IgM单克隆丙种球蛋白病亲属）。