Mutations affecting the structure and function of immunoglobulin M.

Shulman, Marc J.; Heusser, Christoph; Filkin, C; Köhler, Georges

doi:10.1128/mcb.2.9.1033

Cited by 71 publications

(32 citation statements)

References 51 publications

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“…IgM from the two strains had a similar profile after passage over the column, indicating that they have the same size and are assembled in a similar way (Fig. S1A), thus confirming previous observations (43,45). Moreover, IgM from both Cμ13 and BALB/c mice had an HA titer of 1:128 compared at the same IgM concentrations (∼0.87 mg/mL as measured by absorbance at 280 nm).…”

Section: Resultssupporting

confidence: 77%

“…Analysis of IgM with the same point mutation as the one introduced into the genome of the Cμ13 mice showed that the light chain and the μ-chain in mutant and WT IgM had the same size (45) and that >90% of both types of IgM was assembled in the form of pentamers (43). We show here that IgM in sera of Cμ13 and WT mice has the same size, the same ability to agglutinate SRBCs, and a similar half-life.…”

Section: Discussionmentioning

confidence: 99%

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Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

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Section: Resultssupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…This is in contrast to many Ig secretion mutants previously described that have sizable deletions in their Ig genes (32,37) or synthesize only H or L chains (27). Though immunoglobulin binding protein, BiP, has been shown to be involved in proper assembly of Ig, we feel it unlikely that faulty interactions with BiP are responsible for Russell body formation .…”

Section: Mott Cell Hybridomas Often Secrete Igsmentioning

confidence: 61%

Synthesis of abnormal immunoglobulins by hybridomas from autoimmune "viable motheaten" mutant mice.

Schweitzer

Taylor

Shultz

1991

The Journal of Cell Biology

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Abstract. Secretory defects in abnormal plasma cells, called Mott cells, that appear in lymphoid tissues of spontaneously autoimmune, "viable motheaten" (me°/me°) mice lead to deposition of immunoglobulin in RER-bound vesicles. Such vesicles have been termed Russell bodies. Cells with Russell bodies can also be observed rarely in normal animals, usually as a result of extreme antigenic loads or pathologic states . To understand why these abnormal cells appear commonly in mev/me°mice, we have established a panel of hybridomas that contain Russell bodies . Using immunochemical analysis and immunoelectron microscopy, we have characterized the secretory defects. Although these hybridoma cells synthesize a normal size heavy chain and it associates with light chain, the Russell bodies have many characteristics of inclusion bodies, which commonly appear in cells synthesizing mutant proteins and often are associated with incompletely or abnormally folded proteins . Pulse-chase experiments showed that immunoglobulins M UTATIONS that disrupt biological processes provide insight into the ordering of these processes. Many mutations that affect the immune system cause multiple pleiotropic abnormalities, emphasizing the complexity and interrelatedness of the immune, endocrine, and nervous systems (33) . One of the most deleterious mutations identified is "viable motheaten" (me,),' a spontaneous, single gene mutation that occurred on the C57BL/6J background (34) . me, mice have a mean life span of 9 wk. Autoimmune pulmonary lesions are the proximal cause of death. Homozygotes (me°/me,) develop glomerulonephritis, have multiple autoantibodies, and serum IgM levels are increased 25-to 50-fold above levels found in littermate controls (35) . Abnormal plasma cells, called Mott cells, are found initially at -4 wk of age . These cells have discrete gly-1 . Abbreviations used in this paper: BiP, binding protein ; Endo H, endoglycosidase H; me', viable motheaten; PAS, periodic acid-Schiffs ; SACI, Staphylococcus aureus, Cowan strain I ; TEM, transmission electron microscopy.

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“…After the cells were incubated at 37ЊC for 2 days, supplemented medium was added to give a final concentration of 10 g of mycophenolic acid per ml, 15 g of hypoxanthine per ml, and 25 g of xanthine per ml (MHX medium) (28), and cells were plated at 5 ϫ 10 4 cells/ml. After 2 weeks the culture supernatants were tested for C determinants by enzyme-linked immunosorbent assay (ELISA) specific for the C 1 domain (38).…”

Section: Construction Of Targeting Vectorsmentioning

confidence: 99%

Expression of the (Recombinant) Endogenous Immunoglobulin Heavy-Chain Locus Requires the Intronic Matrix Attachment Regions

Oancea

Berrú

Shulman

1997

Molecular and Cellular Biology

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The elements which regulate gene expression have traditionally been identified by their effects on reporter genes which have been transfected into cell lines or animals. It is generally assumed that these elements have a comparable role in expression of the corresponding endogenous locus. Nevertheless, several studies of immunoglobulin heavy-chain (IgH) gene expression have reported that the requirements for expressing IgH-derived transgenes differ from the requirements for expression of the endogenous IgH locus. Thus, although expression of transgenes requires multiple elements from the J H -C intron-the E core enhancer, the matrix attachment regions (MARs) which flank E, and several switch-associated elements-B-cell lines in which expression of the endogenous heavy-chain gene is maintained at the normal level in the absence of these intronic elements have occasionally been reported. Gene targeting offers an alternative method for assessing regulatory elements, one in which the role of defined segments of endogenous genes can be evaluated in situ. We have applied this approach to the IgH locus of a hybridoma cell line, generating recombinants which bear predetermined modifications in the functional, endogenous heavy-chain gene. Our analysis indicates the following. Chromatin fibers appear to exist as loops which are anchored to the nuclear matrix, or scaffold (reviewed in reference 25). The loops are thought to correspond to functional domains in which the transcriptional state of one domain is largely independent of its neighbors. It is generally considered that the sites of anchorage in the DNA have a particular affinity for the matrix and can therefore be identified as matrix attachment regions (MARs) or scaffold attachment regions.As illustrated in Fig.

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Mutations affecting the structure and function of immunoglobulin M.

Cited by 71 publications

References 51 publications

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Synthesis of abnormal immunoglobulins by hybridomas from autoimmune "viable motheaten" mutant mice.

Expression of the (Recombinant) Endogenous Immunoglobulin Heavy-Chain Locus Requires the Intronic Matrix Attachment Regions

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