单克隆免疫球蛋白病代表一大类具有不同症状和体征的相关疾病。[1]Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006;81:693-703.http://www.ncbi.nlm.nih.gov/pubmed/16706268?tool=bestpractice.com[2]Kyle RA. Current concepts on monoclonal gammopathies. Aust N Z J Med. 1992;22:291-302.http://www.ncbi.nlm.nih.gov/pubmed/1497556?tool=bestpractice.com[3]Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.http://www.nejm.org/doi/full/10.1056/NEJMoa054494#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/16571879?tool=bestpractice.com[4]International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757.http://www.ncbi.nlm.nih.gov/pubmed/12780789?tool=bestpractice.com其中最重要的特点是在血清或尿液中存在单克隆蛋白，可以是完整形式的免疫球蛋白，也可以是其中的一部分，或者是游离轻链。单克隆免疫球蛋白是由骨髓/软组织浆细胞瘤/外周血（疾病进展时）中存在的单克隆浆细胞分泌的。
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单克隆蛋白
浆细胞是终末分化的、不具有再生能力的 B 细胞发育阶段的效应细胞。[5]Fairfax KA, Kallies A, Nutt SL, et al. Plasma cell development: from B-cell subsets to long-term survival niches. Semin Immunol. 2008;20:49-58.http://www.ncbi.nlm.nih.gov/pubmed/18222702?tool=bestpractice.com[6]McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol. 2005;23:487-513.http://www.ncbi.nlm.nih.gov/pubmed/15771579?tool=bestpractice.com[7]Radbruch A, Muehlinghaus G, Luger EO, et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 2006;6:741-750.http://www.ncbi.nlm.nih.gov/pubmed/16977339?tool=bestpractice.com[8]Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230-242.http://www.ncbi.nlm.nih.gov/pubmed/15738953?tool=bestpractice.com它们是体液免疫的初始介导者，分泌抗原特异性免疫球蛋白。自身免疫性疾病及浆细胞肿瘤常出现浆细胞异常。一个或更多地浆细胞克隆性突变会导致单克隆免疫球蛋白疾病。[5]Fairfax KA, Kallies A, Nutt SL, et al. Plasma cell development: from B-cell subsets to long-term survival niches. Semin Immunol. 2008;20:49-58.http://www.ncbi.nlm.nih.gov/pubmed/18222702?tool=bestpractice.com[6]McHeyzer-Williams LJ, McHeyzer-Williams MG. Antigen-specific memory B cell development. Annu Rev Immunol. 2005;23:487-513.http://www.ncbi.nlm.nih.gov/pubmed/15771579?tool=bestpractice.com[7]Radbruch A, Muehlinghaus G, Luger EO, et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol. 2006;6:741-750.http://www.ncbi.nlm.nih.gov/pubmed/16977339?tool=bestpractice.com[8]Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230-242.http://www.ncbi.nlm.nih.gov/pubmed/15738953?tool=bestpractice.com正常情况下，浆细胞分泌完整免疫球蛋白，其由 2 个完整的轻链和重链构成。重链有 5 种类型，分别是μ(IgM)、δ(IgD)、γ(IgG)、α(IgA)、ε(IgE)。每一个免疫球蛋白分子重链均只能和 2 种轻链之一结合（κ或者λ）。重链有 4、5 个结构域，而轻链有 2 个结构域，通过二硫键以共价形式结合。
[Figure caption and citation for the preceding image starts]: 免疫球蛋白结构Dr Kumar [Citation ends].
单克隆蛋白可能是潜在淋巴组织恶性疾病的结果，可能是无症状的浆细胞克隆扩增的一部分（如临床意义未知的单克隆丙种球蛋白病），或者可引起危及生命的并发症（如原发性淀粉样变）。[9]Kumar S, Dispenzieri A, Katzmann JA, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood. 2010;116:5126-5129.http://bloodjournal.hematologylibrary.org/content/116/24/5126.longhttp://www.ncbi.nlm.nih.gov/pubmed/20798235?tool=bestpractice.com蛋白电泳是检验血、尿中单克隆蛋白的方法之一。[10]Katzmann JA, Kyle R. Immunochemical characterization of immunoglobulins in serum, urine, and cerebrospinal fluid. In: Detrick B, ed. Manual of molecular and clinical laboratory immunology. 7th ed. Washington, DC: American Society for Microbiology Press; 2006:88-100.[11]Katzmann JA, Dispenzieri A. Screening algorithms for monoclonal gammopathies. Clin Chem. 2008;54:1753-1755.http://www.clinchem.org/cgi/content/full/54/11/1753http://www.ncbi.nlm.nih.gov/pubmed/18957556?tool=bestpractice.com免疫球蛋白的定量通过比浊法实现。
单克隆浆细胞
浆细胞疾病可以伴随单克隆浆细胞的增殖，可以在骨髓、外周血或软组织中检测到。浆细胞疾病中骨髓检查可以发现克隆性浆细胞，其比例可以正常或偏高。
[Figure caption and citation for the preceding image starts]: 单克隆浆细胞Dr Kumar [Citation ends].浆细胞特异性表达 CD138，这一点可以通过免疫组化来鉴定。而浆细胞的单克隆性可以通过轻链限制性表达来鉴定，即表达某一种轻链的浆细胞数量异常增多从而导致κ/λ比值异常。[12]O'Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms. Am J Clin Pathol. 2004;121:254-263.http://ajcp.ascpjournals.org/content/121/2/254.longhttp://www.ncbi.nlm.nih.gov/pubmed/14983940?tool=bestpractice.com浆细胞比值的异常可以对骨髓活检标本用针对λ或 Lambda 轻链抗体进行免疫组织或 PCR 方法证实。
而克隆性浆细胞的数量仅仅在进展期的骨髓瘤和浆细胞白血病中增多，在大部分浆细胞疾病中却并不增高。[13]Witzig TE, Kimlinger TK, Ahmann GJ, et al. Detection of myeloma cells in the peripheral blood by flow cytometry. Cytometry. 1996;26:113-120.http://www.ncbi.nlm.nih.gov/pubmed/8817086?tool=bestpractice.com[14]Albarracin F, Fonseca R. Plasma cell leukemia. Blood Rev. 2011;25:107-112.http://www.ncbi.nlm.nih.gov/pubmed/21295388?tool=bestpractice.com流式细胞仪灵敏度高，可以常规用于骨髓穿刺评估中，以便发现较小数量的克隆性浆细胞并确定浆细胞免疫表型特征。[15]Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482-488.http://ajcp.ascpjournals.org/content/121/4/482.longhttp://www.ncbi.nlm.nih.gov/pubmed/15080299?tool=bestpractice.com[16]Paiva B, Vidriales MB, Cervero J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood. 2008;112:4017-4023.http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18669875http://www.ncbi.nlm.nih.gov/pubmed/8669875?tool=bestpractice.com[17]Rawstron AC, Orfao A, Beksac M, et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008;93:431-438.http://www.haematologica.org/cgi/content/full/93/3/431http://www.ncbi.nlm.nih.gov/pubmed/18268286?tool=bestpractice.com
流行病学
意义未明的单克隆免疫球蛋白病 (MGUS) 是最常见的单克隆浆细胞病，成人患病率为 1-2%。[3]Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369.http://www.nejm.org/doi/full/10.1056/NEJMoa054494#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/16571879?tool=bestpractice.com[18]Axelsson U, Hallen J. Review of fifty-four subjects with monoclonal gammopathy. Br J Haematol. 1968;15:417-420.http://www.ncbi.nlm.nih.gov/pubmed/4176071?tool=bestpractice.com[19]Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569.http://www.nejm.org/doi/full/10.1056/NEJMoa01133202#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/11856795?tool=bestpractice.com[20]Saleun JP, Vicariot M, Deroff P, et al. Monoclonal gammopathies in the adult population of Finistere, France. J Clin Pathol. 1982;35:63-68.http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=497449&blobtype=pdfhttp://www.ncbi.nlm.nih.gov/pubmed/6801095?tool=bestpractice.com[21]Kyle RA, Durie BG, Rajkumar SV, et al; International Myeloma Working Group. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24:1121-1127.http://www.ncbi.nlm.nih.gov/pubmed/20410922?tool=bestpractice.com[22]Wadhera RK, Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. Mayo Clin Proc. 2010;85:933-942.http://www.ncbi.nlm.nih.gov/pubmed/20713974?tool=bestpractice.com其患病率随年龄而增加，70 岁以上明显增多。不同地理和种族人群中患病率也不同：相对于欧美而言，亚洲发病率更低，而黑人比白人患病率更高。
病因
单克隆免疫球蛋白疾病的病因至今仍不清楚，克隆性浆细胞演变的机制一直是基础和临床研究的热点。其流行病学的特点提示可能有些易感因素存在。环境、基因、感染、炎症等都有不同的致病假说，但都缺乏确切的依据。
相关疾病
除 MGUS 之外的一些疾病也可以在血清和/或尿液中检测到单克隆蛋白。包括：
淋巴增殖性疾病中 B 细胞克隆可以分泌单克隆蛋白（CLL、NHL、移植后单克隆球蛋白血症[23]Wadhera RK, Kyle RA, Larson DR, et al. Incidence, clinical course, and prognosis of secondary monoclonal gammopathy of undetermined significance in patients with multiple myeloma. Blood. 2011;118:2985-2987.http://bloodjournal.hematologylibrary.org/content/early/2011/07/15/blood-2011-04-349175.longhttp://www.ncbi.nlm.nih.gov/pubmed/21765020?tool=bestpractice.com）
某些情况下，如 HCV、HIV 感染可以导致单克隆球蛋白病的患病率增高。
在感染或炎症状态下，如系统性红斑狼疮、类风湿性关节炎、银屑病性关节炎、干燥综合征、Schnitzler 综合征，也可以导致一过性的 B 细胞或浆细胞的克隆性增高。
