Prohibitin Is Involved in Patients with IgG4 Related Disease

Abstract

ObjectiveIgG4-related disease (IgG4-RD) is a chronic systemic disease involved in many organs and tissues. As only limited autoantigens have been found since the beginning of this century, the aim of this study was to reveal new candidate autoantigens of IgG4-RD.MethodsMultiple cell lines including HT-29, EA.hy926, HEK 293 and HepG2 were used to test the binding ability of circulating autoantibodies from IgG4-RD sera. The amino-acid sequence was then analyzed by matrix-assisted laser desorption/ionization time-of-flight tandem (MALDI-TOF/TOF) mass spectrometry. After the cloning and expression of recombinant putative autoantigen in a bacterial expression system, the corresponding immuno assay was set up and utilized to observe the prevalence of serum autoantibodies in a large set of confirmed clinical samples.ResultsOne positive autoantigen was identified as prohibitin. ELISA analysis showed that a majority of patients with IgG4-RD have antibodies against prohibitin. Anti-prohibitin antibodies were present in the sera of patients with definite autoimmune pancreatitis (25/34; 73.5%), Mikulicz’s disease (8/15; 53.3%), retroperitoneal fibrosis (6/11; 54.5%), other probable IgG4-RD (26/29; 89.7%) and Sjögren’s syndrome (4/30; 13.3%) but not in apparently healthy donors (1/70; 1.4%).ConclusionsAn association between prohibitin and patients with some IgG4-RD was observed, although the results were quite heterogeneous among different individuals within autoimmune pancreatitis, Mikulicz’s disease and retroperitoneal fibrosis.

Disease Severity Linked to Increase in Autoantibody Diversity in IgG4‐Related Disease

“…Anti–laminin 511‐E8 IgG was detected in only 1% of our IgG4‐RD cohort, which is comparable to the 1.6% response frequency observed among controls by Shiokawa et al, but markedly below the 51% frequency reported in their cohort of IgG4‐related AIP patients . Similarly, although anti‐prohibitin IgG4 was reported to occur in 73% of IgG4‐RD patients with diverse organ manifestations , we found only 10% IgG4 reactivity among the patients in our similarly diverse cohort. One possible explanation for these discrepancies may be related to genetic differences between the studied cohorts.…”

“…In contrast to annexin A11 and laminin 511‐E8, only anti‐prohibitin antibodies had been reported in the context of multiorgan systemic IgG4‐RD , thereby permitting a direct comparison to the present cohort. The frequency of anti‐prohibitin responses observed among the systemic and clinically diverse cohort was 10%.…”

“…Since 2015, 4 autoantigens have been described as potential triggers for IgG4‐RD: prohibitin, annexin A11, laminin 511‐E8, and galectin‐3 . However, validation of these findings using external patient cohorts and characterization of the relationship between these specific autoantigens has yet to be achieved.…”

Association of IgG4‐Related Disease With History of Malignancy

“…One important difference between that study and ours is that we included patients with diverse manifestations of IgG4-RD; in fact, only 19% of the patients in our cohort have had pancreatic involvement, and only 3 of the patients who had a history of malignancy had IgG4-related AIP. The pathogenesis of IgG4-RD remains poorly understood, but it is generally recognized as an immunemediated condition (9) which may be mediated by autoimmunity (18,19), Th2-polarized and T regulatory lymphocytes (20), and/or oligoclonally expanded circulating plasmablasts (8,21). Associations between allergic conditions and IgG4-RD may suggest a shared pathogenesis between the 2 conditions (22).…”

Clinical chronic pancreatitis

“…(18) In another study, Prohibitin (PHB), a gene associated with various functions including mitochondrial function and transcriptional modulation, was identified as a possible auto-antigen. (19)…”