Plasma cell dyscrasias: Difference between revisions
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{{main article|Humoral immunity}} |
{{main article|Humoral immunity}} |
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{{main article|Antibody}} |
{{main article|Antibody}} |
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Plasma cells are key effector elements of the [[adaptive immune system]]. They contribute to immunity by making [[antibodies]] that bind with and neutralize specific foreign [[antigens]]. Plasma cells develop from [[B lymphocyte]]s when they are stimulated to do so by [[T lymphocyte]]s during the processing of these antigens. Developing plasma cells refashion a part of their [[genome]] to create a new gene encoding an antibody specifically targeting the instigating antigen. Formation of this new gene requires [[somatic hypermutation]] to create [[point mutation]]s at the [[IGH@|immunoglobulin heavy chain locus]] on the short or "q" arm of human chromosome 14 at position 32.33 (site notated as 14q32.33) in order to encode a protein that may bind the instigating antigen. This is followed by [[class switch recombination]], i.e. the deletion and subsequent recombination of genetic material at 14q32.33 so that the newly fashioned gene encodes the appropriate IgG, IgD, IgA, IgM, or IgE [[Antibody#Isotype|antibody isotype]]. These genetic mutations and recombinations often go awry by, for example, placing newly formed antibody genes close to, and thereby controlled by, highly active [[Promoter (genetics)|gene promotors]] |
Plasma cells are key effector elements of the [[adaptive immune system]]. They contribute to immunity by making [[antibodies]] that bind with and neutralize specific foreign [[antigens]]. Plasma cells develop from [[B lymphocyte]]s when they are stimulated to do so by [[T lymphocyte]]s during the processing of these antigens. Developing plasma cells refashion a part of their [[genome]] to create a new gene encoding an antibody specifically targeting the instigating antigen. Formation of this new gene requires [[somatic hypermutation]] to create [[point mutation]]s at the [[IGH@|immunoglobulin heavy chain locus]] on the short or "q" arm of human chromosome 14 at position 32.33 (site notated as 14q32.33) in order to encode a protein that may bind the instigating antigen. This is followed by [[class switch recombination]], i.e. the deletion and subsequent recombination of genetic material at 14q32.33 so that the newly fashioned gene encodes the appropriate IgG, IgD, IgA, IgM, or IgE [[Antibody#Isotype|antibody isotype]]. These genetic mutations and recombinations often go awry by, for example, placing newly formed antibody genes close to, and thereby controlled by, highly active [[Promoter (genetics)|gene promotors]], by the formation of an extra chromosome to form a state of chromosome [[trisomy]], or in more than >90% of IgM gammopathy cases a mutation of the [[MYD88]] gene located on chromosome 3 at its p22.2 position that is apparently found in both plasma cells and associated lymphoplamacytic cells.<ref name="pmid28466550">{{cite journal | vauthors = Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino ACW | title = Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma | journal = British Journal of Haematology | volume = | issue = | pages = | year = 2017 | pmid = 28466550 | doi = 10.1111/bjh.14649 | url = }}</ref><ref name="pmid28483372">{{cite journal | vauthors = El-Ayoubi A, Wang JQ, Hein N, Talaulikar D | title = Role of plasma cells in Waldenström macroglobulinaemia | journal = Pathology | volume = 49 | issue = 4 | pages = 337–345 | year = 2017 | pmid = 28483372 | doi = 10.1016/j.pathol.2017.02.004 | url = }}</ref><ref name="pmid28331368">{{cite journal | vauthors = Abeykoon JP, Yanamandra U, Kapoor P | title = New developments in the management of Waldenström macroglobulinemia | journal = Cancer Management and Research | volume = 9 | issue = | pages = 73–83 | year = 2017 | pmid = 28331368 | pmc = 5354523 | doi = 10.2147/CMAR.S94059 | url = }}</ref> As one consequence of these mutations and chromosomal changes: '''a)''' a potentially pre-malignant [[clone]] of proliferating plasma cells becomes established in the [[bone marrow]]; '''b)''' this clone overproduces either intact IgG, IgD, IgA, IgM, or IgE antibodies, just the [[Immunoglobulin heavy chain]] (i.e. either the γ, δ, α, μ or ε chain of IgG, IgD, IgA, IgM, or IgE, respectively) part of these antibodies, or just the kappa (κ) or lambda (λ) [[immunoglobulin light chain]] part of these antibodies; and '''c)''' the clone secretes this overproduced protein which is detected in the blood as the defining evidence of a plasma cell dyscrasia and [[gammopathy]] viz., the [[myeloma protein]] (also termed M protein).<ref name="pmid28466550">{{cite journal | vauthors = Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino ACW | title = Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma | journal = British Journal of Haematology | volume = | issue = | pages = | year = 2017 | pmid = 28466550 | doi = 10.1111/bjh.14649 | url = }}</ref> These events initiate the spectrum or stages of plasma cell dyscrasias that may lead to overt multiple myeloma<ref name="pmid28466550"/> or in the case of clonal IgM over-secretion commonly (>90%) associated with the MYD88L265P mutation in plasma cells plus infiltration of bone marrow by lymphoplamacytic B cells, [[Waldenström's macroglobulinemia]].<ref name="pmid28483372">{{cite journal | vauthors = El-Ayoubi A, Wang JQ, Hein N, Talaulikar D | title = Role of plasma cells in Waldenström macroglobulinaemia | journal = Pathology | volume = 49 | issue = 4 | pages = 337–345 | year = 2017 | pmid = 28483372 | doi = 10.1016/j.pathol.2017.02.004 | url = }}</ref> |
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== Stages of plasma cell dyscrasias == |
== Stages of plasma cell dyscrasias == |
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=== MGUS === |
=== MGUS === |
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{{main article|Monoclonal gammopathy of undetermined significance}} |
{{main article|Monoclonal gammopathy of undetermined significance}} |
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Monoclonal gammopathy of undetermined significance or [[Mgus|MGUS]] is defined as the presence in the blood of a [[monoclonal]] IgG, IgD, IgA, IgE, or IgM antibody or their respective heavy chains at a concentration of <30 gram/liter or the presence of the free light chains of these antibodies at a κ to λ ratio outside of the normal κ to λ ratio reference interval (0.26-1.65) as detected by [[gel electrophoresis]] or, more preferably, [[Immunoelectrophoresis]] of serum. |
Monoclonal gammopathy of undetermined significance or [[Mgus|MGUS]] is defined as the presence in the blood of a [[monoclonal]] IgG, IgD, IgA, IgE, or IgM antibody or their respective heavy chains at a concentration of <30 gram/liter or the presence of the free light chains of these antibodies at a κ to λ ratio outside of the normal κ to λ ratio reference interval (0.26-1.65) as detected by [[gel electrophoresis]] or, more preferably, [[Immunoelectrophoresis]] of serum. Other criteria are required for these [[Paraproteinemia|monoclonal gammopathies]] to be diagnosed as MGUS but tased on their very different clinical findings, criteria for assessing the rate of disease progression, and treatments, the MGUS is further classified into two sub-types: IgM MGUS when IgM is the detected monoclonal protein and non-IgM MGUS (often termed just MGUS) when any of the other monoclonal proteins is detected. For the diagnosis of non-IgM MOGUS, further requirements are that: '''a)''' bone marrow clonal plasma cells are <10% of total nucleated cells; '''b)''' there is an absence of any one of the '''CRAB''' critera (the CRAB criteria are C = [[Hypercalcaemia|Calcium blood levels elevated]], R = [[Renal failure]], A = [[Anemia]], B = Bone lesions, e.g. bone [[plasmacytoma]]s); '''c)''' there is an absence of [[plasmacytoma]](s) of bone or soft tissues, [[amyloidosis]], or other plasma cell disorders; and '''d)''' there is not a highly abnormal ratio of free light chains (i.e. the ratio of serum free light chain ratio that is >100 as measured by the higher light chain [either κ or λ] concentration divided by the lower light chain concentration providing that the higher light chain concentration is >100 mg/liter).<ref name="pmid28479151"/> For the diagnosis of IgM MGUS, the only further requirement is that bone marrow lymphoplamacytic cells (cells that combine the morphologic features of both plasma cells and B cells) be <10% of total nucleated cells.<ref name="pmid28331368">{{cite journal | vauthors = Abeykoon JP, Yanamandra U, Kapoor P | title = New developments in the management of Waldenström macroglobulinemia | journal = Cancer Management and Research | volume = 9 | issue = | pages = 73–83 | year = 2017 | pmid = 28331368 | pmc = 5354523 | doi = 10.2147/CMAR.S94059 | url = }}</ref> |
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MGUS is typically discovered as an incidental finding when protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. The condition occurs more commonly in men and has a 2-fold higher incidence in individuals of African decent than Caucasians. Among MGUS cases expressing an intact antibody, 70%, 15%, 12%, and 3% express either IgG, IgM, IgA, or two of these M proteins, respectively; MGUS cases expressing IgE or IgD are rare. These cases represent ~80% of all MGUS. The remaining ~20 of cases express either κ or λ light chains.<ref name="pmid28479151"/> In general, MGUS is a relatively stable condition that afflicts 3% of people aged 50 and 5% of people aged 70; it progresses to more serious conditions at a rate of 0.5-1% of cases per year for at least its first 25 years. One particular sub-type of MGUS cases that do not express an intact antibody or heavy chain M protein but rather overexpress a free κ or λ light chain at a ratio of <100 (measured as higher light chain concentration divided by lower light chain concentration progress at the much slower pass of 0.3 per 100 years.<ref name="pmid28479151"/><ref name="pmid28466550"/> However, these same patients, when expressing a free light chain ration of >100 progress at a rate of 30% to 80% over 2 years.<ref name="pmid27161311"/> |
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Plasma cell dyscrasias are produced as a result of abnormal proliferation of a monoclonal population of plasma cells that may or may not secrete detectable levels of a monoclonal immunoglobulin or immunoglobulin fragment ([[myeloma protein|paraprotein]] or M protein). Although the most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), closely related disorders include [[multiple myeloma]], solitary [[plasmacytoma]] of bone, extramedullary plasmacytoma, [[Waldenström's macroglobulinemia]] (WM), [[primary amyloidosis]], [[light chain deposition disease]], [[paraproteinemia]], and [[heavy chain disease|heavy-chain disease]]. The spectrum of MGUS, solitary plasmacytoma of bone, and asymptomatic and symptomatic multiple myeloma may represent a natural progression of the same disease.<ref>{{cite web | url=http://www.accessmedicine.com/content.aspx?aid=2794254 | title=Chapter 8. Multiple Myeloma and Other Plasma Cell Dyscrasias | accessdate=September 20, 2016 | archiveurl=https://web.archive.org/web/20110707080735/http://www.accessmedicine.com/content.aspx?aid=2794254 | archivedate=July 7, 2011 | deadurl=y}}</ref> |
Plasma cell dyscrasias are produced as a result of abnormal proliferation of a monoclonal population of plasma cells that may or may not secrete detectable levels of a monoclonal immunoglobulin or immunoglobulin fragment ([[myeloma protein|paraprotein]] or M protein). Although the most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), closely related disorders include [[multiple myeloma]], solitary [[plasmacytoma]] of bone, extramedullary plasmacytoma, [[Waldenström's macroglobulinemia]] (WM), [[primary amyloidosis]], [[light chain deposition disease]], [[paraproteinemia]], and [[heavy chain disease|heavy-chain disease]]. The spectrum of MGUS, solitary plasmacytoma of bone, and asymptomatic and symptomatic multiple myeloma may represent a natural progression of the same disease.<ref>{{cite web | url=http://www.accessmedicine.com/content.aspx?aid=2794254 | title=Chapter 8. Multiple Myeloma and Other Plasma Cell Dyscrasias | accessdate=September 20, 2016 | archiveurl=https://web.archive.org/web/20110707080735/http://www.accessmedicine.com/content.aspx?aid=2794254 | archivedate=July 7, 2011 | deadurl=y}}</ref> |
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Revision as of 17:26, 13 June 2017
 | This article needs additional citations for verification. (February 2013) |
| Plasma cell dyscrasias | |
|---|---|
| Specialty | Hematology |
Plasma cell dyscrasias is a term for the many pre-malignant and malignant disorders of plasma cells. The seriousness of these hematological disorders varies broadly but in all cases the plasma cell dyscrasias are either malignant diseases such as multiple myeloma and Waldenström's macroglobulinemia or have the potential to become these malignant diseases.[1] Thus, individual diseases in the spectrum of plasma cell dyscrasias require either immediate treatment or careful periodic clinical monitoring for disease progression which will require this treatment.[2]
Plasma cell malignancy
Plasma cells are key effector elements of the adaptive immune system. They contribute to immunity by making antibodies that bind with and neutralize specific foreign antigens. Plasma cells develop from B lymphocytes when they are stimulated to do so by T lymphocytes during the processing of these antigens. Developing plasma cells refashion a part of their genome to create a new gene encoding an antibody specifically targeting the instigating antigen. Formation of this new gene requires somatic hypermutation to create point mutations at the immunoglobulin heavy chain locus on the short or "q" arm of human chromosome 14 at position 32.33 (site notated as 14q32.33) in order to encode a protein that may bind the instigating antigen. This is followed by class switch recombination, i.e. the deletion and subsequent recombination of genetic material at 14q32.33 so that the newly fashioned gene encodes the appropriate IgG, IgD, IgA, IgM, or IgE antibody isotype. These genetic mutations and recombinations often go awry by, for example, placing newly formed antibody genes close to, and thereby controlled by, highly active gene promotors, by the formation of an extra chromosome to form a state of chromosome trisomy, or in more than >90% of IgM gammopathy cases a mutation of the MYD88 gene located on chromosome 3 at its p22.2 position that is apparently found in both plasma cells and associated lymphoplamacytic cells.[3][4][5] As one consequence of these mutations and chromosomal changes: a) a potentially pre-malignant clone of proliferating plasma cells becomes established in the bone marrow; b) this clone overproduces either intact IgG, IgD, IgA, IgM, or IgE antibodies, just the Immunoglobulin heavy chain (i.e. either the γ, δ, α, μ or ε chain of IgG, IgD, IgA, IgM, or IgE, respectively) part of these antibodies, or just the kappa (κ) or lambda (λ) immunoglobulin light chain part of these antibodies; and c) the clone secretes this overproduced protein which is detected in the blood as the defining evidence of a plasma cell dyscrasia and gammopathy viz., the myeloma protein (also termed M protein).[3] These events initiate the spectrum or stages of plasma cell dyscrasias that may lead to overt multiple myeloma[3] or in the case of clonal IgM over-secretion commonly (>90%) associated with the MYD88L265P mutation in plasma cells plus infiltration of bone marrow by lymphoplamacytic B cells, Waldenström's macroglobulinemia.[4]
Stages of plasma cell dyscrasias
MGUS
Monoclonal gammopathy of undetermined significance or MGUS is defined as the presence in the blood of a monoclonal IgG, IgD, IgA, IgE, or IgM antibody or their respective heavy chains at a concentration of <30 gram/liter or the presence of the free light chains of these antibodies at a κ to λ ratio outside of the normal κ to λ ratio reference interval (0.26-1.65) as detected by gel electrophoresis or, more preferably, Immunoelectrophoresis of serum. Other criteria are required for these monoclonal gammopathies to be diagnosed as MGUS but tased on their very different clinical findings, criteria for assessing the rate of disease progression, and treatments, the MGUS is further classified into two sub-types: IgM MGUS when IgM is the detected monoclonal protein and non-IgM MGUS (often termed just MGUS) when any of the other monoclonal proteins is detected. For the diagnosis of non-IgM MOGUS, further requirements are that: a) bone marrow clonal plasma cells are <10% of total nucleated cells; b) there is an absence of any one of the CRAB critera (the CRAB criteria are C = Calcium blood levels elevated, R = Renal failure, A = Anemia, B = Bone lesions, e.g. bone plasmacytomas); c) there is an absence of plasmacytoma(s) of bone or soft tissues, amyloidosis, or other plasma cell disorders; and d) there is not a highly abnormal ratio of free light chains (i.e. the ratio of serum free light chain ratio that is >100 as measured by the higher light chain [either κ or λ] concentration divided by the lower light chain concentration providing that the higher light chain concentration is >100 mg/liter).[1] For the diagnosis of IgM MGUS, the only further requirement is that bone marrow lymphoplamacytic cells (cells that combine the morphologic features of both plasma cells and B cells) be <10% of total nucleated cells.[5]
MGUS is typically discovered as an incidental finding when protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias. The condition occurs more commonly in men and has a 2-fold higher incidence in individuals of African decent than Caucasians. Among MGUS cases expressing an intact antibody, 70%, 15%, 12%, and 3% express either IgG, IgM, IgA, or two of these M proteins, respectively; MGUS cases expressing IgE or IgD are rare. These cases represent ~80% of all MGUS. The remaining ~20 of cases express either κ or λ light chains.[1] In general, MGUS is a relatively stable condition that afflicts 3% of people aged 50 and 5% of people aged 70; it progresses to more serious conditions at a rate of 0.5-1% of cases per year for at least its first 25 years. One particular sub-type of MGUS cases that do not express an intact antibody or heavy chain M protein but rather overexpress a free κ or λ light chain at a ratio of <100 (measured as higher light chain concentration divided by lower light chain concentration progress at the much slower pass of 0.3 per 100 years.[1][3] However, these same patients, when expressing a free light chain ration of >100 progress at a rate of 30% to 80% over 2 years.[2]
Plasma cell dyscrasias are produced as a result of abnormal proliferation of a monoclonal population of plasma cells that may or may not secrete detectable levels of a monoclonal immunoglobulin or immunoglobulin fragment (paraprotein or M protein). Although the most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), closely related disorders include multiple myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, Waldenström's macroglobulinemia (WM), primary amyloidosis, light chain deposition disease, paraproteinemia, and heavy-chain disease. The spectrum of MGUS, solitary plasmacytoma of bone, and asymptomatic and symptomatic multiple myeloma may represent a natural progression of the same disease.[6]
Classification
- Cryoglobulinemia
- Heavy chain disease
- Monoclonal gammopathy of undetermined significance
- Multiple myeloma
- Plasmacytoma
- Plasma cell leukemia
- POEMS syndrome
- Primary amyloidosis (Immunoglobulin light chain amyloidosis)
- Waldenström's macroglobulinemia
References
- ^ a b c d Willrich M, Murray DL, Kyle RA (2017). "Laboratory testing for monoclonal gammopathies: Focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". Clinical Biochemistry. doi:10.1016/j.clinbiochem.2017.05.001. PMID 28479151.
{{cite journal}}: Vancouver style error: initials in name 1 (help) - ^ a b van de Donk NW, Mutis T, Poddighe PJ, Lokhorst HM, Zweegman S (2016). "Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". International Journal of Laboratory Hematology. 38 Suppl 1: 110–22. doi:10.1111/ijlh.12504. PMID 27161311.
- ^ a b c d Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino A (2017). "Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma". British Journal of Haematology. doi:10.1111/bjh.14649. PMID 28466550.
{{cite journal}}: Vancouver style error: initials in name 5 (help) - ^ a b El-Ayoubi A, Wang JQ, Hein N, Talaulikar D (2017). "Role of plasma cells in Waldenström macroglobulinaemia". Pathology. 49 (4): 337–345. doi:10.1016/j.pathol.2017.02.004. PMID 28483372.
- ^ a b Abeykoon JP, Yanamandra U, Kapoor P (2017). "New developments in the management of Waldenström macroglobulinemia". Cancer Management and Research. 9: 73–83. doi:10.2147/CMAR.S94059. PMC 5354523. PMID 28331368.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ "Chapter 8. Multiple Myeloma and Other Plasma Cell Dyscrasias". Archived from the original on July 7, 2011. Retrieved September 20, 2016.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help)