Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins

Brändle, Simone Maren; Obermeier, Birgit; Şenel, Makbule; Bruder, Jessica; Mentele, Reinhard; Khademi, Mohsen; Olsson, Tomas; Tumani, Hayrettin; Kristoferitsch, Wolfgang; Lottspeich, Friedrich; Wekerle, Hartmut; Hohlfeld, Reinhard; Dornmair, Klaus

doi:10.1073/pnas.1522730113

Cited by 157 publications

(122 citation statements)

References 46 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…There is one clear limitation to the study by Brändle et al (4). Although they generated six OCB rAbs from four MS patients, they were successful in identifying the specificity of only three antibodies originating from two patients.…”

mentioning

confidence: 98%

“…Identification of those antigens recognized by OCB antibodies is thought to hold fundamental clues to the pathogenesis of MS. In a recent PNAS publication, Brändle et al (4) provide evidence that OCB in MS target ubiquitous intracellular antigens released in cellular debris.…”

mentioning

confidence: 99%

“…Dornmair and coworkers used a combination of new biochemical, proteomic, and transcriptomic approaches (4,14) to examine the specificity of antibodies in MS OCB. Disulfide-linked IgG heavy-(IgH) and IgG light-(IgL) chain complexes were purified from single OCB spots using affinity chromatography and two-dimensional gel electrophoresis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Antibodies in multiple sclerosis oligoclonal bands target debris

Winger

Zamvil

2016

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

View full text Add to dashboard Cite

IgG oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) of more than 90% of multiple sclerosis (MS) patients and are considered the immunological hallmark that supports MS diagnosis. OCB are not unique to MS but are also observed in chronic CNS infections, where they target their causative agents (1-3). However, the target specificities of the IgG within OCB in MS have remained a mystery. Identification of those antigens recognized by OCB antibodies is thought to hold fundamental clues to the pathogenesis of MS. In a recent PNAS publication, Brändle et al. (4) provide evidence that OCB in MS target ubiquitous intracellular antigens released in cellular debris.In 1942, Kabat et al. (5) established the diagnostic value of quantitative determinations of CSF gamma globulins in clinical neurology, and particularly in MS. They observed that changes in CSF IgG were independent of those in serum, suggesting that this Ig production was compartmentalized to the CNS. Advances in CSF analytics and gel electrophoresis led to the identification of OCB in 1959 (6). CSF OCB in MS patients are persistent, which is thought to be a reflection of both ongoing CNS inflammation and immunologic memory. Understanding the specificity of OCB has since captivated the interest of clinical neurologists and scientists alike. It has been assumed that the OCB target antigens are relevant to MS pathogenesis. The most popular theory contends that IgG within OCB target myelin autoantigens and/or viruses that may elicit CNS damage directly or indirectly via molecular mimicry. Some earlier studies that evaluated whole CSF IgG from MS patients identified antibodies to several different viruses, such as measles, varicella zoster, human T-lymphocytic virus 1, and human hepatitis virus 6 (7), whereas other investigations found antibodies targeting major myelin proteins, myelin basic protein (MBP) and myelin oligodencrocyte glycoprotein (MOG) (8, 9) as well as glycolipids, fatty acids, and neurofilament proteins (10). Similarly, more recent investigations that have applied single-cell PCR cloning to individual CSF B cells in MS have detected antibodies to certain viruses or myelin proteins (11-13). However, it has been impossible to match specificity of antibodies identified in CSF to OCB by studying whole CSF IgG or recombinant antibodies constructed from rearranged Ig heavy-and light-chain genes in individual B cells.Dornmair and coworkers used a combination of new biochemical, proteomic, and transcriptomic approaches (4, 14) to examine the specificity of antibodies in MS OCB. Disulfide-linked IgG heavy-(IgH) and IgG light-(IgL) chain complexes were purified from single OCB spots using affinity chromatography and two-dimensional gel electrophoresis. Those antibody (IgH 2 IgL 2 ) complexes were then analyzed by mass spectrometry to generate patient-specific Ig peptidomes. In parallel, IgH and IgL genes, including the unique complementarity-determining region 3, from CSF B cells isolated from the corresponding patient were sequenced ...

show abstract

mentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Antibodies in multiple sclerosis oligoclonal bands target debris

Winger

Zamvil

2016

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

View full text Add to dashboard Cite

show abstract

“…Recent work by others [13] demonstrated that antibodies contributing to the oligoclonal banding observed in MS patients are directed against ubiquitous intracellular proteins. However, eleven of the rhAbs we tested are brain-specific by ELISA (Brain+ Kidney- Flu- OVA-) and fourteen of the rhAbs we tested are brain-specific by ICC (Sy5y+ Hep-2-).…”

Section: Discussionmentioning

confidence: 99%

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

et al. 2016

View full text Add to dashboard Cite

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.

show abstract

“…Wekerle and colleagues screened recombinant cerebrospinal fluid oligoclonal immunoglobulin bands for binding to antigen libraries. They noted binding to a set of intracellular structures that hardly qualify as classic demyelinating antibody candidates (26). On the other hand, Alexander Gabibov (Russian Academy of Sciences, Moscow) reported that one of the main MS autoantigens, myelin basic protein, escapes ubiquitination control for proteasomal degradation.…”

Section: Therapeutic Avenuesmentioning

confidence: 99%

Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity

Zouali

Tsay

2016

Mol Med

View full text Add to dashboard Cite

Immunologists have long investigated B lymphocytes as solely antibody-producing cells. With further studies, it became clear that B cells can exert a variety of functions within the immune system and beyond. As a result, B cells are considered promising targets for immunotherapy in a variety of disorders. Recently, experts in B cell biology and autoimmunity convened to discuss important stepping stones to decipher the complexity of B lymphocyte-mediated pathways in autoimmune diseases. Twenty-five years ago, the first report describing the clinical efficacy of depleting B lymphocytes in autoimmune diseases was published (1). This also marked organization of the first International Conference on B Cells and Autoimmunity, held in 2001 in Bergen, Norway. Since then, the credentials of B cells as essential players in autoimmune disease have been well established. For its sixth edition, this conference series settled along the shores of Sun Moon Lake in the heart of Taiwan on August 16-18, 2016, to view and discuss recent advances in different facets of B cell biology and put them in the perspective of understanding autoimmunity and designing effective immunointervention strategies. Following the tradition established in 2001, the conference was a forum where basic immunologists and their clinically trained colleagues met to discuss hot topics of autoimmunity research. Speakers from four continents discussed some of their new data and insights and brought considerable excitement to the conference in the refreshingly beautiful and elegant landscape of Sun Moon Lake and its indescribable charm. B L Y M P H O C Y T E S A N D A U T O I M M U N I T Y

show abstract

Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins

Cited by 157 publications

References 46 publications

Antibodies in multiple sclerosis oligoclonal bands target debris

Antibodies in multiple sclerosis oligoclonal bands target debris

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity

Contact Info

Product

Resources

About