单克隆丙种球蛋白病代表一大类相关疾病。[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 May;81(5):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 Jun;22(3):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 Mar 30;354(13):1362-9.
https://www.nejm.org/doi/full/10.1056/NEJMoa054494
http://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 Jun;121(5):749-57.
http://www.ncbi.nlm.nih.gov/pubmed/12780789?tool=bestpractice.com
其中最常见的共同特征是在血清或尿液中存在单克隆蛋白，可以是完整形式、片段，以及/或者游离轻链。同时会伴随骨髓/软组织（浆细胞瘤）/外周循环（在更晚期的疾病中）中存在单克隆浆细胞。
浆细胞和单克隆蛋白
浆细胞是 B 细胞系终末分化（通常不再增殖的特化细胞）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 Feb;20(1):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 Oct;6(10):741-50.
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 Mar;5(3):230-42.
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 Feb;20(1):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 Oct;6(10):741-50.
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 Mar;5(3):230-42.
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 条相同的轻链和 2 条相同的重链构成。重链有 5 大类型，分别对应免疫球蛋白的主要类型：μ（IgM）、δ（IgD）、γ（IgG）、α（IgA）、ε（IgE）。每一个免疫球蛋白分子的重链只和两条轻链中的一条结合（κ 或者 λ）。重链有 4 个或 5 个结构域，而轻链有 2 个结构域，两者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].
单克隆蛋白是单个浆细胞克隆产生的异常免疫同质性免疫球蛋白或其片段。它们可能是基础淋巴组织恶性肿瘤的结果，可能是无症状性浆细胞克隆扩增的一部分（例如，意义未明的单克隆丙种球蛋白病），还可能引起致死性并发症（例如，原发性淀粉样变性）。[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 Dec 9;116(24):5126-9.
http://bloodjournal.hematologylibrary.org/content/116/24/5126.long
http://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 Nov;54(11):1753-5.
http://www.clinchem.org/cgi/content/full/54/11/1753
http://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。血清中的免疫球蛋白游离轻链通过使用对免疫球蛋白轻链部分具有特异性的抗体进行评估。
浆细胞的克隆扩增
浆细胞克隆扩增是单克隆丙种球蛋白病的潜在异常表现。这些浆细胞可见于骨髓、外周循环或软组织内。它们通常可在骨髓检查中发现，其中克隆性浆细胞的存在可能伴随或不伴随浆细胞比例的绝对增加。尽管浆细胞可通过免疫组化检查细胞表面是否呈 CD138（多配体蛋白聚糖）染色阳性来识别，但证明有克隆性则取决于轻链限制、表达 κ 或 λ 的浆细胞中的一种过量生成导致正常 κ/λ 比值发生偏斜。[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 Feb;121(2):254-63.
http://www.ncbi.nlm.nih.gov/pubmed/14983940?tool=bestpractice.com
对骨髓活检样本进行使用抗 κ 或 λ 轻链抗体的免疫组化分析或聚合酶链反应（polymerase chain reaction, PCR）检测可证明比值偏斜。
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 Jun 15;26(2):113-20.
http://www.ncbi.nlm.nih.gov/pubmed/8817086?tool=bestpractice.com
[14]Albarracin F, Fonseca R. Plasma cell leukemia. Blood Rev. 2011 May;25(3):107-12.
http://www.ncbi.nlm.nih.gov/pubmed/21295388?tool=bestpractice.com
灵敏的流式细胞术技术可用于常规分析骨髓抽吸液，以检测即使少量的异常浆细胞，并对其进行免疫表型表征。[15]Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004 Apr;121(4):482-8.
http://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 Nov 15;112(10):4017-23.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581991
http://www.ncbi.nlm.nih.gov/pubmed/18669875?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 Mar;93(3):431-8.
https://haematologica.org/article/download/4784/18859
http://www.ncbi.nlm.nih.gov/pubmed/18268286?tool=bestpractice.com
[Figure caption and citation for the preceding image starts]: 单克隆浆细胞Dr Kumar [Citation ends].
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 Mar 30;354(13):1362-9.
https://www.nejm.org/doi/full/10.1056/NEJMoa054494
http://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 Oct;15(4):417-20.
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 Feb 21;346(8):564-9.
https://www.nejm.org/doi/full/10.1056/NEJMoa01133202#t=article
http://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 Jan;35(1):63-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC497449
http://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 Jun;24(6):1121-7.
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 Oct;85(10):933-42.
http://www.ncbi.nlm.nih.gov/pubmed/20713974?tool=bestpractice.com
其患病率随年龄而增加，男性患病率通常比女性高，70 岁以上者患病率通常更高。[3]Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30;354(13):1362-9.
https://www.nejm.org/doi/full/10.1056/NEJMoa054494
http://www.ncbi.nlm.nih.gov/pubmed/16571879?tool=bestpractice.com
[23]Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Best Pract Res Clin Haematol. 2005;18(4):689-707.
https://www.doi.org/10.1016/j.beha.2005.01.025
http://www.ncbi.nlm.nih.gov/pubmed/16026745?tool=bestpractice.com
不同地理和种族人群中患病率也不同：与欧洲、北美和南美相比，亚洲患病率更低，而黑人比白人患病率更高。[24]Landgren O, Katzmann JA, Hsing AW, et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin Proc. 2007 Dec;82(12):1468-73.
http://www.ncbi.nlm.nih.gov/pubmed/18053453?tool=bestpractice.com
在单克隆丙种球蛋白病患者的一级亲属中观察到患病率增加。[25]Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009 Jul 23;114(4):785-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716020
http://www.ncbi.nlm.nih.gov/pubmed/19179466?tool=bestpractice.com
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。 其中包括：
淋巴增殖性疾病中 B 细胞克隆可以分泌单克隆蛋白（慢性淋巴细胞白血病、非霍奇金淋巴瘤、移植后单克隆球蛋白血症）[26]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 Sep 15;118(11):2985-7.
http://bloodjournal.hematologylibrary.org/content/early/2011/07/15/blood-2011-04-349175.long
http://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。
与一过性出现若干反应性 B 细胞/浆细胞群克隆相关的感染性或炎症性疾病（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）。
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