On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease

Abstract

The pathophysiology of immunoglobulin G4-related disease (IgG4-RD) and its most common manifestations, IgG4-associated (sclerosing) cholangitis and autoimmune pancreatitis, remains largely unknown, but IgG4 is presumably involved. IgG4 is a promiscuous antibody, which could be directly pathogenic, fulfill a protective role, or could just be a fortuitous marker of an aberrant inflammatory response. IgG4 antibodies possess exclusive structural and functional characteristics suggesting anti-inflammatory and tolerance-inducing effects. By studying the role of IgG4 in other inflammatory conditions, namely hypersensitivity and allergies, autoimmune and immune-mediated diseases, infections and malignancies, new insights can be obtained increasing our understanding of the role of IgG4 antibodies in IgG4-RD. Beekeepers, animal laboratory workers and individuals undergoing allergen immunotherapy possess high serum levels of allergen-specific IgG4, which exhibit immunosuppressive functions, protecting the individual from anaphylactic reactions. In autoimmune/immune-mediated diseases, such as pemphigus vulgaris, pemphigus foliaceus and MuSK-myasthenia gravis, IgG4 autoantibodies are pathogenic. Regarding malignancies such as melanoma and cholangiocarcinoma or helminthic infections, IgG4 antibodies inhibit clearance of tumor cells or the invader, respectively. Translating these findings to IgG4-RD, IgG4 alone can implement pathogenic effects and structural damage, but may also function as a protective antibody dampening the more harmful effects of IgG1 when directed against the same epitopes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases

“…Antibodies against HERV-K env-su [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] were found in the sera of 81% ALS patients, whereas only 3% of HCs were positive and none of MS and AD patients [area under the curve (AUC) 0.96, P < 0.0001, ALS vs. MS; ALS vs. AD, P < 0.0001] ( Fig.…”

“…The occurrence of a double positivity of autoantibodies in serum and CSF in the three groups was also searched for, in order to find a peptide suitable to serve as a possible serum biomarker also predictive of CSF positivity. Sixteen out of 17 sera antibody positive to HERV-K env-su [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] were also positive in CSF (94%). This finding may indicate that this peptide could represent a possible serum biomarker in ALS pathology (P < 0.0001) ( Table 1).…”

“…A correlation analysis was performed to establish the association between the antibody positivity toward the selected peptides in serum and CSF in the different pathologies. In patients with ALS [16], a very good correlation was found between antibody HERV-K envsu [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] peptide in serum compared to CSF (R 2 = 0.6; P < 0.002) (Fig. 3a).…”

“…Another correlation analysis was performed to establish the association between the antibody positivity of the HERV-K env-su selected peptides in serum/ CSF of ALS patients and the ALS Functional Rating Scale revised (ALSFRS) [18,19]. A good correlation Figure 3 Scatter plot showing the correlations between IgG against HERV-K env [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] in CSF with HERV-K env [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] was found between antibody HERV-K env-su [19][20][21][22][23][24][25][26][27][28]…”

“…Human endogenous retrovirus K (HERV-K) peptides as possible biomarker for ALS Serum samples of ALS patients were collected and analysed and were found to be positive to IgG against HERV-K surface peptides, before or contemporary to clinical/electromyography diagnosis. HERV-K envsu [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] was recognized in all samples whereas antibodies against HERV-K env 109-126 were recognized in 93% of samples (Table S3).…”