Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

Silverman, Gregg J.; Goldfien, Robert; P, Chen; Mageed, Rizgar A.; Jefferis, Royston; Goñi, Fernando; Frangione, Blas; Fong, Sherman; Carson, Dennis A.

doi:10.1172/jci113620

Cited by 79 publications

(45 citation statements)

References 44 publications

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“…[68][69][70] This is consistent with finding the V H genes commonly expressed in B-CLL BCRs to be those associated with autoreactivity. [71][72][73] Second, susceptibility to autoreactivity and autoimmunity is frequently linked within families, which would be consistent with the apparent propensity of family members of B-CLL patients to develop clonal amplifications. 47,48 Third, the structures of the B-CLL BCRs in certain instances are very reminiscent of antibodies that react with capsular polysaccharides of microorganisms, 8,74,75 e.g., Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitides.…”

Section: A Model For the Development And Evolution Of B-cll Cellsmentioning

confidence: 82%

Biology and Treatment of Chronic Lymphocytic Leukemia

Keating¹,

Chiorazzi²,

Messmer³

et al. 2003

Hematology

105

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Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process.Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored.Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed.In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance.The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies. I. UNRAVELING THE BIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIANicholas Chiorazzi, MD,* Bradley Messmer, PhD, Rajendra N. Damle, PhD, Steven L. Allen, MD, Kanti R. Rai,MB,BS, and Manlio Ferrarini, MD In recent years, our view of the biological features classically ascribed to the leukemic B ...

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Section: A Model For the Development And Evolution Of B-cll Cellsmentioning

confidence: 82%

Biology and Treatment of Chronic Lymphocytic Leukemia

Keating¹,

Chiorazzi²,

Messmer³

et al. 2003

Hematology

105

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“…This finding indicates that the G6 idiotype is not encoded by hv1263-related genes, which were present in all six of these subjects. It is possible that somatic substitutions might occasionally generate a G6-positive Ig from a non-51p1-related gene (27,28). However, such B cells should not have affected this study because G6 analysis was restricted to IgDpositive cells, whose expressed Ig V genes generally have not incurred somatic mutations (16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…In human paraprotein IgM rheumatoid factors, the G6 idiotype is common and is almost invariably associated with a V L chain encoded by the Ig V gene, kv325 (10,28). Thus, autospecificity for Fc appears favored in the germline-encoded V H /V L combination of a 51p-related gene plus kv325, even though D and J H variations sometimes modify RF activity (35).…”

Section: Discussionmentioning

confidence: 99%

Expression of the immunoglobulin VH gene 51p1 is proportional to its germline gene copy number.

Sasso¹,

Johnson²,

Kipps³

1996

J. Clin. Invest.

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51p1 is an immunoglobulin V H gene that is frequently expressed in B cell chronic lymphocytic leukemia and early in B cell ontogeny. The 51p1 gene locus is highly polymorphic, consisting of 13 alleles that can be classified as being either 51p1-related or hv1263-related, based on distinctive sequence motifs in the second complementarity determining region. Two of the 51p1-related genes usually occur as a linked pair on the same haplotype, resulting from gene duplication. Consequently, a person can have a total of zero to four copies of 51p1-related genes. These genes are detectable in genomic DNA by sequence-specific RFLP analysis using oligonucleotide probes. Ig encoded by nonmutated 51p1-related genes can be detected by G6, a murine antiidiotypic mAb. We have now studied lymphocytes from 35 human tonsils to examine the relation between the number of 51p1-related germline gene copies and the proportion of IgD-bearing tonsillar B cells that react with G6. All subjects who had zero copies of 51p1-related genes lacked any G6-reactive B cells, whereas those with four copies of 51p1-

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“…The Ab Kim 13.1, AND, and NEI carry the VH I -associated idiotype, G6 (48), which has been found in about one-quarter of CLL (32), one-third of paraprotein IgM RF (49), and 17% of fetal splenocytes (50). Comparison of these expressed VH sequences with their probable germline sources in the 51pl allelic set indicates that G6 positivity is associated with the protein sequences of 51 p1, which could derive from variants 1, 2, 5, or 11 and at least one allele encoding a non-5 p I protein, variant 7.…”

Section: Discussionmentioning

confidence: 99%

A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles.

Sasso

Dijk²,

Bull³

et al. 1993

J. Clin. Invest.

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The immunoglobulin V H gene 51p1, a member of the large V H1 gene family, is preferentially expressed by B cells in the fetus and in chronic lymphocytic leukemia (CLL) and appears to be the source for many cryoglobulin rheumatoid factors. Polymorphism of Sipi may therefore be functionally important. We have studied the germline representation of 51pl and closely related V H elements to establish their prevalence and allelic relationship. A panel of oligonucleotide probes directed to the complementarity determining regions (CDR1 and CDR2) of 51pl and a similar gene, hv1263, was used in restriction fragment polymorphism analysis of 48 unrelated individuals and six families. 13 V H alleles to the 51pl locus were identified, each distinguished by its restriction fragment size, hybridization profile, or both. On some haplotypes the locus was duplicated. Null alleles were not seen. The 13 alleles were cloned, yielding nine distinct nucleotide sequences that were > 98.2% identical and included 51pl and hv1263. These germline variations could influence specificity for antigen, because the corresponding protein sequences differed by up to five amino acids, including three nonconservative changes in the CDR. Two of the most prevalent variants contained 51pl. These findings expand the spectrum of polymorphism seen among human VH genes and elucidate the germline origin of V H1 sequences frequently expressed in autoantibodies and CLL. We conclude that the 5lpl locus is polymorphic, and that the 51pl element is the predominant member of a complex set of alleles. (J. Clin.

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Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

Abstract: Rheumatoid factors (RFs)

Cited by 79 publications

References 44 publications

Biology and Treatment of Chronic Lymphocytic Leukemia

Biology and Treatment of Chronic Lymphocytic Leukemia

Expression of the immunoglobulin VH gene 51p1 is proportional to its germline gene copy number.

A fetally expressed immunoglobulin VH1 gene belongs to a complex set of alleles.

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