Familial Paraproteinemia: Hyper-Responsive B-Cells as Endophenotype

May 31, 2017 | Autor: Helga Ogmundsdottir | Categoria: Endophenotypes, Humans, Female, Male, Aged, Middle Aged, B Lymphocytes, Immunoglobulin A, Middle Aged, B Lymphocytes, Immunoglobulin A
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IWWM 2010 Proceedings

Familial Paraproteinemia: Hyper-Responsive B-Cells as Endophenotype Helga M. Ögmundsdóttir,1 Hlíf Steingrímsdóttir,1,2 Vilhelmína Haraldsdóttir2 Clinical Lymphoma, Myeloma & Leukemia, Vol. 11, No. 1, 82-84, 2011; DOI: 10.3816/CLML.2011.n.014

Abstract The prevalence of paraproteinemias or monoclonal gammopathies increases with age. No other major risk factors have been recognized, but significant associations have been reported with chronic antigen exposure, agricultural environment, and family history. In around 130 families reported worldwide, IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) occurs with multiple myeloma (MM) whereas Waldenström’s macroglobulinemia (WM) is linked to IgM MGUS. Of the 8 multicase families described here, 5 are remarkable for including both IgG/IgA and IgM type disorders. In the remaining 3 families IgG/ IgA MGUS and MM occurred with Hodgkin disease and T-cell malignancies. These different patterns of familial paraproteinemia indicate different genetic backgrounds. A previously described functional phenotype of hyper-responsive B lymphocytes fulfils criteria for being an endophenotype and may be related to raised serum IgM. Identifying an endophenotype is important to ensure correct classification of affected family members and thus enhance the power of genetic studies.

Introduction Paraproteinemia or monoclonal gammopathy (MG) reflects the persistent expansion of one clone of B cells. Monoclonal gammopathy of unknown significance (MGUS) is subclinical, very rare before middle age, but after age 50 the prevalence increases steadily from about 1% to 3% at age 70.1 MG could thus be regarded as a consequence of ageing of the immune system. MGUS of IgA or IgG type can progress to multiple myeloma (MM) at an estimated rate of 1% per year. Similarly, IgM MGUS can progress to Waldenström’s macroglobulinemia (WM), estimated rate 1.5% per year.2 When

1Faculty

of Medicine, University of Iceland 2Department of Clinical Haematology, Landspítali University Hospital Reykjavík, Iceland Address for correspondence: Helga M. Ögmundsdóttir, Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101 Reykjavik, Iceland E-mail: [email protected] 2152-2650/$ - see frontmatter © 2011 Elsevier Inc. All rights reserved.

monoclonal cells become identifiable they have acquired genetic and chromosomal alterations.3-5 B-cell malignancies may depend on constant signaling through the B-cell receptor.6,7 Thus, chronic antigenic stimulation could be expected to increase the risk for malignant transformation, as has been reported for MG.8,9 Risk of development of lymphomas and MG has been linked to specific environmental exposures, such as dioxin,10 or more generally, to an agricultural environment.9 The occurrence of paraproteinemias in families has been described in the medical literature for more than half a century. Most often IgG/IgA monoclonal gammopathy of undetermined significance (MGUS) occur in the same families as MM, whereas IgM MGUS shows a familial link with WM.11 Four families had been reported before the current study with IgG/IgA and IgM disorders occurring together; 2 of these were Icelandic.11

The Endophenotype Concept The most commonly cited definition of an endophenotype, or intermediate phenotype, was published by Gottesman and Gould in 2003. This states (slightly abbreviated) that an endophenotype (1) is associated with the illness in the population, (2) is heritable, (3) manifests whether or not illness is active but may have to be elicited, (4) within families, co-segregates with the illness, (5) is found in non-affected family members at higher rate than in the general population. The classical example of an endophenotype is the abnormal glucose tolerance test before the development of clinical diabetes but in recent years the concept has been extensively used for genetic studies of psychiatric diseases.12-14 If monoclonal gammopathies are regarded as a consequence of an ageing process the familial predisposition might be expected to manifest as deviations in the response of B cells to stimulation thus enhancing this process.

IgG/IgA and IgM Monoclonal Gammopathies Occur Together in Icelandic Families In our cancer registry¬–based study of pedigrees of 218 patients with MM we found a significant 2-fold risk of having MM, but risk of MGUS was not increased. WM could not be included as this was not registered as a malignancy until 1991.15 A population-based Swedish study found a 20-fold risk of developing WM among relatives of WM patients but no increased risk of MM.16 From the 218

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| Clinical Lymphoma, Myeloma & Leukemia February 2011

Table 1 IgG/IgA and IgM Disorders and Other Hematological Malignancies in Familial Paraproteinemia MGUS Family Number 1a

IgG/IgA 1

2a

Not known 1

3

3a

3

4

1

5

1

6

2

7a

1

8a

IgM

MM

WM

NHL

3

1

2

2

1

1 1

1 1

HD

T-NHL

ALL

1

2

1

2

3

1

1

1

1

1

2

3

2

2

1

2

1 1

My

2

2 1

CLL

1 3

1

1

aFamilies

with IgG/IgA and IgM disorders. Abbreviations: ALL = acute lymphocytic leukemia; CLL = chronic lymphocytic leukemia; HD = Hodgkin disease; MGUS = monoclonal gammopathy of undetermined significance; MM = multiple myeloma; My = myeloid leukemia (acute or chronic); NHL = non-Hodgkin lymphoma; T-NHL = T-cell non-Hodgkin lymphoma; WM = Waldenström’s macroglobulinemia

Icelandic MM pedigrees 8 MG families were identified where the proband with MM had a relative with MM, and/or at least 1 relative with MGUS and/or at least 1 relative with another hematologic malignancy. Other types of malignancies are not prevalent. These pedigrees were traced further and analyzed by comparison with the Icelandic Cancer Registry and by screening for paraprotein. The disease occurrence in these 8 families is summarized in Table 1. Remarkably, in 5 of the 8 families IgG/IgA and IgM disorders occur together, 3 of them having cases with WM, including 1 with multiple cases. In the remaining 3 families 2 have multiple cases of Hodgkin disease and 2 include T-cell–derived diseases. No evidence was found of autoimmunity (ie, chronic antigen exposure) in these families. These findings indicate that there may be several types of families with inherited predisposition to paraproteinemias and therefore also different genetic backgrounds. Detailed analysis of single families can thus reveal patterns and tentative associations that are not apparent from large epidemiological studies.

Hyper-Responding B-Lymphocytes as Endophenotype for Familial Monoclonal Gammopathies A functional phenotype defined as hyper-responsive B cells was first described in 9 healthy members of family #8. Briefly, peripheral blood mononuclear cells were cultured with 5 μg/mL of poke-weed mitogen, culture supernatants collected and concentrations of IgG and IgM measured. Immunoglobulin production of more than 2 standard deviations above control cultures on day 7 was defined as hyper-response.17 This phenotype has now been found in 2 individuals in family #3, and 1 each in families #2 and #4, ie, in 4 of the 5 families with IgG/IgA and IgM disorders. The number of individuals available for testing was much lower in these families than family #8. Table 2 shows an abbreviated summary of detected hyper-responders in 4 generations of this family, emphasizing those that have been tested repeatedly. The hyper-responder phenotype has persisted for up to 20 years in 8 family members. It is of note that 3 of these, in 3 generations, showed raised polyclonal serum IgM when this family was first studied in 1978-1980.18 The 3 hyper-responders who are children of a case with MM did not

Table 2 Paraproteinemias and Hyper-Responders in Family Number 8 Generation I WM

Generation II

Generation III

H, 1/2

H

IgM MGUS H, 2/3a

Generation IV

No offspring H, 2/3 H, 3/3a

H, 2/3 H

WM

H, 1/3

H, 2/2a

MGUS

H H, 2/2

MM

H, 2/2 H, 2/2 Not tested

H

aRaised

serum IgM in 1978-1980. H = Hyper-responder. Outcome of repeated testing is indicated as x/y, where x is the number of occasions when hyper-responsiveness was detected and y is the total number of tests for that individual. Cases with paraproteinemia in the first generation with no offspring tested or affected have been omitted.

show raised se IgM at that time, when they were between 20 and 30 years old. The most recently diagnosed case of MGUS in the family had increased se IgM in 1978, but was not identified as a hyperresponder on the only occasion tested in 1990 when the assay was still being developed. Raised polyclonal se IgM and in vitro hyperresponsiveness of B cells may therefore reflect the same underlying phenomenon, but the in vitro test is more sensitive. Persistent elevation of se IgM may take time to develop. McMaster et al19 observed persistent immunoglobulin abnormalities in three multi-case WM families, including raised polyclonal IgM. The same author also found that the evidence for genetic linkage was strengthened by including IgM MGUS cases as patients in WM families.20 Refining the definition of affected individuals in the family further by including a functional endophenotype can be expected to provide enhanced power to genetic studies. Referring back to the definition

Clinical Lymphoma, Myeloma & Leukemia February 2011

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Proceedings From the 6th International Workshop on Waldenström’s Macroglobulinemia given above, the hyper-responder phenotype appears to fulfill the criteria listed for an endophenotype, and is likely to be closer to the underlying gene action than serum immunoglobulin levels.

Future Directions The development of different types of B-cell–derived neoplasias can be related to certain stages and events in the germinal centre reaction when B cells undergo a step-wise differentiation process governed by key transcription factors, BCL-6, Blimp-1 and Pax5.21 This transcriptional program is directly disrupted by dioxin.22 In our current work we are analyzing the differentiation process of isolated B cells from hyper-responders in an in vitro germinal centre model, with respect to expression of activation and differentiation markers and transcription factors.

Conclusion The families presented here demonstrate that IgG/A and IgM disorders can occur together in the same family and thus presumably share a common genetic background. As most families reported so far have either IgG/A or IgM disorders this indicates that there may be several different types of genetic susceptibilities for monoclonal gammopathies. It is conceivable that the cooccurrence of IgG/A and IgM MGs described here is peculiar to an Icelandic mutation. This is made less likely by the fact that these 5 families do not share common ancestry as far as 6 generations back. The notion that a specific endophenotype may be recognizable in healthy potential gene mutation carriers should help in correct classification of affected and non-affected family members. Both of these observations should be considered in future genetic studies.

Acknowledgements The financial support of The Icelandic Research Fund is gratefully acknowledged.

References 1. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance

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and smoldering multiple myeloma. Curr Hematol Malig Rep 2010; 5:62-9. 2. Ansell SM, Kyle RA, Reeder CB, et al. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo stratification of macroglobulinemia and riskadapted therapy (mSMART) guidelines. Mayo Clin Proc 2010; 85:824-33. 3. Berger R, Nguyen-Khac F. [Chromosomal abnormalities and Waldenstrom macroglobulinemia]. Pathol Biol (Paris) 2008; 56:400-6. 4. Braggio E, Keats JJ, Leleu X, et al. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia. Cancer Res 2009; 69:3579-88. 5. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2002; 2:175-87. 6. Bahler DW, Levy R. Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc Natl Acad Sci U S A 1992; 89:6770-4. 7. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88-92. 8. Koshiol J, Gridley G, Engels EA, et al. Chronic immune stimulation and subsequent Waldenstrom macroglobulinemia. Arch Intern Med 2008; 168:1903-9. 9. Morgan GJ, Davies FE, Linet M. Myeloma aetiology and epidemiology. Biomed Pharmacother 2002; 56:223-34. 10. Baccarelli A, Hirt C, Pesatori AC, et al. t(14;18) translocations in lymphocytes of healthy dioxin-exposed individuals from Seveso, Italy. Carcinogenesis 2006; 27:2001-7. 11. Ogmundsdottir HM, Einarsdottir HK, Steingrimsdottir H, et al. Familial predisposition to monoclonal gammopathy of unknown significance, Waldenstrom’s macroglobulinemia, and multiple myeloma. Clin Lymphoma Myeloma 2009; 9:27-9. 12. Gottesman, II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160:636-45. 13. Gould TD, Gottesman, II. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 2006; 5:113-9. 14. Kendler KS, Neale MC. Endophenotype: a conceptual analysis. Mol Psychiatry 2010; 15:789-97. 15. Ogmundsdottir HM, Haraldsdottirm V, Johannesson GM, et al. Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families. Haematologica 2005; 90:66-71. 16. Kristinsson SY, Bjorkholm M, Goldin LR, et al. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood 2008; 112:3052-6. 17. Ogmundsdottir HM, Johannesson GM, Sveinsdottir S, et al. Familial macroglobulinaemia: hyperactive B-cells but normal natural killer function. Scand J Immunol 1994; 40:195-200. 18. Bjornsson OG, Arnason A, Gudmunosson S, et al. Macroglobulinaemia in an Icelandic family. Acta Med Scand 1978; 203:283-8. 19. McMaster ML, Csako G, Giambarresi TR, et al. Long-term evaluation of three multiple-case Waldenstrom macroglobulinemia families. Clin Cancer Res 2007; 13:5063-9. 20. McMaster ML, Goldin LR, Bai Y, et al. Genomewide linkage screen for Waldenstrom macroglobulinemia susceptibility loci in high-risk families. Am J Hum Genet 2006; 79:695-701. 21. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8:22-33. 22. Zhang Q, Bhattacharya S, Kline DE, et al. Stochastic modeling of B lymphocyte terminal differentiation and its suppression by dioxin. BMC Syst Biol 2010; 4:40.

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