The Role of Pathogenic Autoantibodies in Autoimmunity

Rowley, Merrill J.; Whittingham, Senga

doi:10.3390/antib4040314

Cited by 10 publications

(11 citation statements)

References 283 publications

(332 reference statements)

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“…IgA anti‐PDC‐E2 antibodies have been detected not only in serum but also in bile, saliva, and urine; and the presence of IgA anti‐PDC‐E2 in serum and in saliva has been associated with histological progression of PBC . Biliary epithelial cells have the capacity to export dimeric IgA to the bile through polymeric Ig receptor–mediated transcytosis .…”

Section: Discussionmentioning

confidence: 99%

“…IgA anti-PDC-E2 antibodies have been detected not only in serum but also in bile, saliva, and urine; and the presence of IgA anti-PDC-E2 in serum and in saliva has been associated with histological progression of PBC. (30)(31)(32) Biliary epithelial cells have the capacity to export dimeric IgA to the bile through polymeric Ig receptor-mediated transcytosis. (33,34) Our data demonstrate that the majority of PDC-E2specific and PDC-E2/xenobiotic-cross-reactive plasmablasts (75% and 58%, respectively) are IgA.…”

Section: Discussionmentioning

confidence: 99%

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Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

et al. 2017

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A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multi-lineage immune responses to mitochondrial self-antigens in primary biliary cholangitis (PBC), the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC-E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti-PDC-E2 autoantibodies cross-react with the chemical xenobiotics 2-octynoic acid (2-OA) and 6,8-bis (acetylthio) octanoic acid (SAc) and further that there is a high frequency of PDC-E2 specific peripheral plasmablasts. Herein we generated 104 recombinant mAbs based on paired heavy- and light-chain variable regions of individual plasmablasts derived from PBC patients. We identified 32 mAbs reactive with native PDC-E2, including 20 specific for PDC-E2 and 12 cross-reactive with both PDC-E2 and 2-OA and SAc. A lower frequency of replacement somatic hypermutations, indicating lower level of affinity maturation, was observed in the complementarity-determining regions (CDR) of the cross-reactive mAbs in comparison to mAbs exclusively recognizing PDC-E2 or those for irrelevant antigens. In particular, when the highly mutated heavy chain gene of a cross-reactive mAb was reverted to the germline sequence, the PDC-E2 reactivity was reduced dramatically whereas the xenobiotics reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid (LA), a mitochondrial fatty acid that is covalently bound to PDC-E2. Our data reflect that chemically modified LA or LA itself, via molecular mimicry, is the initial target that leads to the development of PBC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

et al. 2017

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“…The role of organ-specific autoantibodies in infertility is not known. Antibodies could be pathogenic, due to tissue damage or could indicate an etiology such as autoimmunity (Naparstek & Plotz 1993, Rowley 2015). …”

Section: Discussionmentioning

confidence: 99%

Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer

Yu-Rice¹,

Edassery²,

Urban³

et al. 2017

Reproduction

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Infertility is a risk factor for ovarian cancer (OvCa). The goal was to determine if antibodies to Selenium Binding Protein 1 (SBP1), an autoantibody we identified in patients with premature ovarian failure (POF), occurs in both infertility and OvCa patients, and thus could be associated with preneoplasia. Anti-SBP1 was measured by immunoassay against recombinant SBP1, in sera from OvCa (n=41), infertility (n=92) and control (n=87) patients. Infertility causes were POF, unexplained, irregular ovulation or endometriosis. The percent of anti-SBP1 positive sera was higher in POF (p=0.02), irregular ovulation (p=0.001), unexplained causes (p=0.02), late (III–IV) stage OvCa (p=0.02) but was not significant in endometriosis, benign ovarian tumors/cysts, early stage (I–II) OvCa or uterine cancer compared to healthy controls. Anti-SBP1 was significantly higher in women with serous (p=0.04) but not non-serous (p=0.33) OvCa compared to controls. Also, we determined if anti-SBP1 was associated with CA125 or anti-p53, markers often studied in OvCa. Anti-p53 and CA125 were measured by established immunoassays. The ability of anti-SBP1 alone to discriminate infertility or OvCa from controls, or when combined with anti-p53 and CA125, to identify OvCa was evaluated by comparing the Area Under the Curve (AUC) in ROC analysis. Anti-SBP1 alone discriminated infertility (AUC=0.7; p=0.001) or OvCa (AUC=0.67; p=0.03) from controls. The sensitivity and specificity of OvCa identification was increased by combining CA125, anti-p53 and anti-SBP1 (AUC=0.96). Therefore, anti-SBP1 occurs in infertile women with POF, ovulatory disturbances or unexplained infertility and in serous OvCa. This suggests an autoimmune process is associated with development of serous OvCa.

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“…where the pathogenic role of autoantibodies are well described (reviewed in (Rowley & Whittingham, 2015). Interestingly, in vivo neutralisation using immune-modulation by pooled IgG has been reported for anti-VGCC Abs, attributed to the blocking action of anti-idiotypic antibodies (Wan et al, 2008).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

A cell-based assay for the detection of pathogenic anti-voltage-gated calcium channel autoantibodies in immunoglobulin G from patients with type 1 diabetes

Alshehri

Mendis

Jackson

2018

Journal of Immunological Methods

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Recent studies have postulated the presence of functional autoantibodies (Abs) against L-type voltage gated calcium channels (VGCCs) in the serum of patients with type 1 diabetes, with various proposed physiological consequences, both islet cell associated and extra-glandular. Arguably, the most potentially damaging effect reported for these Abs is induction of apoptosis in pancreatic beta (β) cells, yet a convincing pathogenic mechanism remains to be demonstrated. In the current study, we report an assay of reactive oxygen species (ROS) stress induction in the rat insulinoma cell line Rin A12, as determined by 2', 7'-Dichlorofluorescein diacetate (DCF-DA) fluorescence detection by flow cytometry. We demonstrate that incubation of Rin A12 cells with immunoglobulin G (IgG) containing anti-VGCC activity from patients with T1D mediates a significant increase in ROS, with subsequent induction of apoptosis, as determined by positivity for annexin V expression. Neither T1D patient-derived IgG lacking anti-VGCC activity or IgG from healthy donors altered ROS or annexin V expression, indicating the new assay is specific for the detection of functional anti-VGCC Abs. Subsequent screening of IgG samples derived from individual patients indicated a prevalence of approximately 75% in a cohort of 20 patients with T1D. The new cell-based assay provides, for the first time, experimental evidence supporting a plausible pathophysiological mechanism underlying anti-VGCC Ab-mediated apoptosis induction in β cells. Additionally, the assay is a considerable advance on previously published methods for detecting and characterising the functional activity of anti-VGCC Abs in patient-derived samples.

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The Role of Pathogenic Autoantibodies in Autoimmunity

Cited by 10 publications

References 283 publications

Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics

Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer

A cell-based assay for the detection of pathogenic anti-voltage-gated calcium channel autoantibodies in immunoglobulin G from patients with type 1 diabetes

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