Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Manheimer-Lory, A; Zandman‐Goddard, Gisele; Davidson, Anne; Aranow, Cynthia; Diamond, Betty

doi:10.1172/jci119796

Cited by 50 publications

(39 citation statements)

References 45 publications

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“…Four light chains were encoded by a V 3 gene, 3 by a V 1 gene, and 1 by a V 2 gene. V gene usage for non-DNAbinding, kidney-binding antibodies was heterogeneous, similar to V gene usage for DNA-binding antibodies (20,21). V H or V family usage did not distinguish kidney-binding antibodies that cross-reacted with DNA from those that did not.…”

Section: Characterization Of Kidney-binding Antibodiesmentioning

confidence: 85%

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Chowdhry¹,

Kowal²,

Hardin³

et al. 2005

Arthritis & Rheumatism

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Objective. Systemic lupus erythematosus (SLE) is characterized by the production of multiple autoantibodies. Anti-DNA antibodies are associated with glomerulonephritis in SLE. It has been shown that anti-DNA antibodies cross-react with bacterial polysaccharide and, thus, might be elicited by microbial exposure. Non-DNA-binding antibodies also contribute significantly to the pathogenesis of lupus nephritis. The goal of this study was to characterize non-DNA-binding, kidneybinding antibodies.Methods. We generated a combinatorial library derived from spleen cells of a patient with SLE who had just previously received pneumococcal vaccine. The phage library was used in an in vivo biopanning technique to identify non-DNA-binding, kidney-binding antibodies. Antibodies were then analyzed for binding to bacterial polysaccharide and to renal antigens.Results. Eight antibodies were characterized that bound glomeruli, but not DNA. All antibodies isolated by this protocol were IgG class, suggesting that there is affinity maturation for glomerular binding. Four of the antibodies cross-reacted with pneumococcal polysaccharide. Six of the antibodies bound to renal antigens that have previously been reported to be cross-reactive with DNA; the other 2 bound to histone.Conclusion. This study suggests that both DNAbinding and non-DNA-binding antibodies in SLE may be elicited by the same bacterial antigens.

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Section: Characterization Of Kidney-binding Antibodiesmentioning

confidence: 85%

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Chowdhry¹,

Kowal²,

Hardin³

et al. 2005

Arthritis & Rheumatism

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“…However, the persistent production of pathogenic autoAbs by the host mediates the chronic, destructive clinical manifestations of Ab-mediated autoimmune diseases, like systemic lupus erythematosus (SLE) (16)(17)(18)(19). This article addresses the behavior of postGC B cells and PCs in a murine model of SLE.…”

mentioning

confidence: 99%

A genetic lesion that arrests plasma cell homing to the bone marrow

Erickson

Lin

Duan

et al. 2003

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

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The coordinated regulation of chemokine responsiveness plays a critical role in the development of humoral immunity. After antigen challenge and B cell activation, the emerging plasma cells (PCs) undergo CXCL12-induced chemotaxis to the bone marrow, where they produce Ab and persist. Here we show that PCs, but not B cells or T cells from lupus-prone NZM mice, are deficient in CXCL12-induced migration. PC unresponsiveness to CXCL12 results in a marked accumulation of PCs in the spleen of mice, and a concordant decrease in bone marrow PCs. Unlike normal mice, in NZM mice, a majority of the splenic PCs are long-lived. This deficiency is a consequence of the genetic interactions of multiple systemic lupus erythematosus susceptibility loci.

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“…Some disease states are associated with atypical patterns of somatic mutation in expressed Igs (5)(6)(7)(8). We therefore analyzed the pattern of mutations observed in GC B cells from these SHIVinfected monkeys to determine whether they are indicative of abnormalities.…”

Section: Bias In Somatic Mutation Of Ig V Regionsmentioning

confidence: 99%

“…B cells in lymph nodes and spleens become activated early in the course of infection, resulting in increases in the size and number of secondary lymphoid follicles and in hyperplasia of germinal centers (GCs) 6 . As immunodeficiency progresses, the GCs are reduced in size and number.…”

mentioning

confidence: 99%

“…Specific features of the somatic mutations observed in expressed Igs have been well-characterized (3,4) and are similar in humans and mice. Some disease states are associated with atypical patterns of somatic mutation in expressed Igs (5)(6)(7)(8)(9). In light of the follicular abnormalities seen in the setting of HIV/SIV infections, the processes that transpire in GCs may also show abnormalities in HIV/SIV-infected individuals.…”

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confidence: 99%

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Germinal Center Function in the Spleen during Simian HIV Infection in Rhesus Monkeys

Margolin

Saunders

Bronfin

et al. 2006

The Journal of Immunology

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Infection with HIV-1, SIV, or simian HIV is associated with abnormalities in the number, size, and structure of germinal centers (GCs). To determine whether these histopathologic abnormalities are associated with abnormalities in Ab development, we analyzed nucleotide sequences of Igs from splenic GCs of simian HIV-infected macaques. Virus-specific GCs were identified in frozen splenic tissue sections by inverse immunohistochemistry using rHIV-1 gp120 as a probe. B cells from envelope-specific GCs were isolated from these sections using laser capture microdissection. Their Igs were amplified from cDNA using nested PCR, then cloned and sequenced. Nucleotide sequences were recovered from nine multimember clonal lineages. Within each lineage, sequences had similar V-D-J or V-J junctions but differed by somatic mutations distributed throughout the variable domain. The clones were highly mutated, similar to that previously reported for HIV-1-specific human IgG Abs. The average clone had 37 mutations in the V region, for a frequency of 0.11 mutations/base. The mutational pattern was strikingly nonrandom, with somatic mutations occurring preferentially at RGYW/WRCY hotspots. Transition mutations were favored over transversions, with C→T and G→A replacements together accounting for almost one-third of all mutations. Analysis of replacement and silent mutations in the framework and CDRs suggests that the Igs were subjected to affinity selection. These data demonstrate that the process of Ab maturation is not seriously disrupted in GCs during the early stages of immunodeficiency virus infection, and that Env-specific Igs developing in GCs are subject to extensive somatic mutation and profound selection pressures.

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Lupus-specific antibodies reveal an altered pattern of somatic mutation.

Cited by 50 publications

References 45 publications

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

Autoantibodies that bind glomeruli: Cross‐reactivity with bacterial antigen

A genetic lesion that arrests plasma cell homing to the bone marrow

Germinal Center Function in the Spleen during Simian HIV Infection in Rhesus Monkeys

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