Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody—antigen interaction

Corper, Adam L.; Sohi, Maninder K.; Bonagura, V.R.; Steinitz, Michael; Jefferis, Royston; Feinstein, A.; Beale, D.; Taussig, Michael J.; Sutton, Brian J.

doi:10.1038/nsb0597-374

Cited by 210 publications

(144 citation statements)

References 37 publications

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“…The region of Sm D3 that is involved in binding to Sm BЈ in vivo consists primarily of aa [21][22][23]39, and 69 -75 of D3 (5). Interestingly, D3-positive patients make high levels of autoantibodies against aa 60 -68 and 76 -106, surrounding but conspicuously avoiding one of the major regions (aa 69 -75) involved in direct intermolecular bonding to Sm BЈ in vivo.…”

Section: Discussionmentioning

confidence: 99%

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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Autoantibodies directed against spliceosomal proteins are a common and specific feature of systemic lupus erythematosus. These autoantibodies target a collection of proteins, including Sm B, B′, D1, D2, and D3. We define the common antigenic targets of Sm D2 and D3 and examine their role in spliceosomal autoimmunity. Our results define nine major common epitopes, five on Sm D2 and four on Sm D3. These epitopes have significantly higher (more basic) isoelectric points than do nonantigenic regions. In fact, this association is of sufficient power to make isoelectric point an excellent predictor of spliceosomal antigenicity. The crystallographic structure of Sm D2 and D3 is now partially described. The anti-Sm D2 and D3 antigenic targets are located on the surface of the respective three-dimensional complexed proteins, thereby suggesting that these epitopes are accessible in the native configuration. All but one of these nine epitopes conspicuously avoid the specific regions involved in intermolecular interactions within the spliceosomal complex. One of the D3 epitopes (RGRGRGMGR) has significant sequence homology with a major antigenic region of Sm D1 (containing a carboxyl-terminal glycine-arginine repeat), and anti-D3 Abs cross-react with this epitope of Sm D1. These results demonstrate that spliceosomal targets of autoimmunity are accessible on native structure surfaces and that cross-reactive epitopes, as well as structural associations of various spliceosomal Ags, may be involved in the induction of autoimmunity in systemic lupus.

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Section: Discussionmentioning

confidence: 99%

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

McClain

Ramsland

Kaufman

et al. 2002

The Journal of Immunology

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“…No evidence of any malignant lymphoproliferative disorder was disclosed by physical examination, thorax-and abdomen-computed tomography or by bone marrow biopsy in the remaining cases. Seven HCVnegative patients with MC syndrome were selected as negative controls (patients [18][19][20][21][22][23][24]. Mixed cryoglobulinemia syndrome was associated with Sjogren's syndrome in three cases (patients [20][21][22], with chronic hepatitis B virus infection (HBs Ag and HBV DNA-positive in serum) in patient 18 and undifferentiated connective tissue disease in patient 23.…”

Section: Patientsmentioning

confidence: 99%

“…The plates were then washed and incubated with a horseradish peroxidase-labeled goat anti-human IgM (Sigma-chemical Laboratories, St Louis, MO, USA). As negative control, the assays were performed with IgM purified from patients with cryoglobulinemia but HCV seronegative (patients [18][19][20][21][22][23][24]. Positive controls consisted of mouse monoclonal antibodies specific for HCV antigens (IBT-Immunological and Biochemical Testsystems GmbH-Germany, and Novocastra, Benton lane, Newcastle upon Tyne UK).…”

Section: Binding Of Hepatitis C Virus Antigensmentioning

confidence: 99%

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations

Sansonno

Simula

et al. 2006

Leukemia

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We demonstrate that in three cases of MC (two with immunocytoma), the IgM-RF þ component of their cryoprecipitated represents the circulating counterpart of the B-cell receptor (BCR) of the monoclonal overexpanded B-cell population. These IgMs were isolated and used to demonstrate a crossreactivity against both hepatitis C virus (HCV) NS3 antigen and the Fc portion of IgG. Epitopes were identified in a fraction of exemplary samples by using epitope excision approach (NS 31250-1334 and IgG Fc 345-355 ). The same phenomenon of crossreactivity has been shown to occur in vivo after immunization of a mouse with the NS3 1251À1270 peptide. To verify if the same reaction was also present in MC samples characterized by an oligo/polyclonal B-cell proliferation, IgM crossreactivity was tested in 14 additional samples. Five out of the 14 were reactive against HCV NS3 and 11 out of 14 were reactive against IgG-Fc peptide. The data support the role of HCV NS3 antigen in a subset of patients with MC, whereas the high frequency of the IgG-Fc epitope suggests that these B cells originate from precursors strongly selected for auto-IgG specificity. We suggest that engagement of specific BCRs by NS3 (or NS3-immunocomplex) antigen could explain the prevalence of IgM cryoglobulins in these patients

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“…Several autoantibodies are produced in conjunction with manifestations of RA (Goldbach-Mansky et al 2000). Rheumatoid factors are the characteristic autoantibodies, binding to the Fc region of agalactosylated IgG (IgG 0 ) molecules (Carson et al 1987;Corper et al 1997) and found in elevated levels in the sera of RA patients. IgG 0 has been directly implicated in the pathogenesis of RA (Bond et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples

et al. 2005

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Single nucleotide polymorphisms in the mannose-binding lectin (MBL2) gene, as well as the serum MBL2 level, have been associated with various autoimmune diseases. We investigated whether such polymorphisms and/or the serum MBL2 level were associated with rheumatoid arthritis (RA) in an Indian population. The frequency of the B variant (codon 54) of the MBL2 gene was quite frequent in the healthy Indian population and was significantly (P=6.35·10 À6 ) lower in RA patients. We replicated this association (P=1.78·10 À5 ) in an independent cohort of control individuals. Promoter polymorphism at À550 nt showed a significant overrepresentation (P=0.003) of the minor allele G in severe RA patients compared with the less severe group. Haplotype LYA frequency was significantly (P=0.03) high in the less severe group, while the frequency of the HYA haplotype was significantly (P=0.04) increased in the severe RA patients. No statistically significant difference in serum MBL2 was observed as a whole, but the individuals homozygous for the LYA haplotype had significantly lower (P=0.017) serum MBL2 levels compared with individuals homozygous for the HYA haplotype. Therefore, the B variant of the MBL2 gene may be associated with protection from RA in our study population, and the promoter polymorphism (À550 nt) seems to have some role in disease progression.

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Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody—antigen interaction

Cited by 210 publications

References 37 publications

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

Anti-Sm Autoantibodies in Systemic Lupus Target Highly Basic Surface Structures of Complexed Spliceosomal Autoantigens

HCV-NS3 and IgG-Fc crossreactive IgM in patients with type II mixed cryoglobulinemia and B-cell clonal proliferations

Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples

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