The antigenic targets of pathological Igs are relatively well-known in the context of allergy and auto-immune diseases. In the context of B-cell malignancies, the main objective is to eliminate the malignant clone and most studies aim to characterize tumoral cells and uncover the mechanisms of their resistance to treatments. Consequently, the antigenic targets of the Igs produced by malignant B-cell clones are rarely studied. Yet there is mounting evidence that chronic antigen stimulation as an important pathogenic mechanism in the development of B-cell malignancies. For instance, patients with somatically–mutated (antigen-driven) chronic lymphocytic leukemia (CLL) have a more favorable clinical course than other CLL patients (31, 32). Evidence in favor of chronic antigen stimulation has also been reported in MGUS and in myeloma (20–26). CLL-associated antigens appear to be mostly autoantigens, notably cytoskeleton components, or autoantigens found in apoptotic cells and bacteria (33–35). Cases of virus (HCV), HIV-driven CLL, MGUS or myeloma appear to be relatively rare (36). In MGUS and myeloma, the targets of monoclonal IgG reported include viruses (>25% cases, predominantly EBV and more rarely, herpes virus simplex (HSV) and HCV) and glucolipids, particularly GlcSph (LGL1) (~15% cases) or associated enzymes (22–26). Using a new assay based on the protein micro-array technology, Bosseboeuf et al. report that the purified monoclonal Ig from 42% of IgA MGUS and myeloma patients recognize EBV EBNA-1, HCV or LGL1. Altogether, a pathogenic model of antigen-driven disease may be valid for about half of CLL, MGUS, and myeloma cases. This model offers new therapeutic approaches: in addition to current therapeutic protocols aimed at eliminating the malignant clone, one can envision therapies designed to reduce or suppress the antigen responsible for disease initiation, i.e., the target of the patient's monoclonal Ig, whenever the target can be identified (28–30).

Unfortunately, the identification of the targets of pathogenic human IgG and IgA for diagnosis and therapeutic purposes is still not possible outside research laboratories. Similarly, the targets of IgMs from healthy individuals are rarely investigated and remain poorly known. To facilitate the study of human IgM antibodies, which are characterized by polyspecificity and autoreactivity, Pashov et al. propose a new peptide array consisting of 594 mimotopes that reflect the common IgM repertoire of 10,000 healthy donors.

To interpret the results of IgG functional studies, the conditions of preparation and purification of Igs are of great importance. Lopez et al. report that low pH exposure during IgG purification may result in aggregates that abnormally and avidly bind Fcγ receptors. These authors compared Protein G purification of IgG (at low pH) with an immunoaffinity method which elutes IgG at physiological pH, and investigated several factors known to impact Fc functionality and influence FcγR binding, including IgG subclass, N-glycosylation, aggregation, and conformational changes. They show that low pH elution of IgG enhances their recognition of FcγRs, and increases IgG aggregation. Thus, differences in IgG purification methods may explain the poor reproducibility of studies of Fc-mediated antibody functions.

The important role played in immunity by the N-linked glycosylation of the Fc region of Igs is well-established but the function of N-linked glycosylation of the variable domains of Igs is less well-known. In their review, Vletter et al. report that N-linked glycans are present on autoantibodies, notably in rheumatoid arthritis, and in patients with B-cell follicular lymphoma (FL). N-linked glycosylation of the variable domain of Igs may confer a selective advantage, through interaction with lectins and/or microbiota. They analyzed the characteristics of autoantibodies and those of Igs from FL patients and healthy donors and found differences in variable domain glycan distribution, frequency and glycan composition, which led them to propose a classification of diseases according to the specific Ig variable domain glycosylation patterns observed in patients.

Sialylation may also modify therapeutic IgGs. Shaffert et al. analyzed changes in human intravenous IgG (IVIg) sialylation upon injection in mice deficient in B cells or lacking the sialyltransferase 1, which catalyzes the addition of α2,6 linked sialic acid residues and conclude that the glycosylation of therapeutic IgGs is stable in vivo Schaffert et al.. Only a very small fraction of IgGs acquired sialic acid structures, mostly in the Fab portion, not in the Fc portion.

The interest of understanding the Ig response of patients in context of acute infection is illustrated by the report by Bloomfield et al., who describe the case of an infant who presented with a normal C-reactive protein (CRP) level despite severe septic shock following Staphylococcus aureus infection, with clear biological evidence of systemic inflammation. Bloomfield et al. suspected a defect in the interleukin-6 (IL-6)/CRP axis, which was confirmed by the presence of neutralizing anti-IL-6 autoantibodies in the child's serum. These findings are of importance since clinical interference of IL-6 signaling, for instance with IL-6 receptor-targeting therapeutic antibodies such as tocilizumab or sarilumab, may alter IL-6-mediated innate immune responses and compromise host resistance to infections.

The complex role played by Igs in chronic infection is illustrated in the review by McLean et al. on the mechanisms of tuberculosis reactivation in individuals with comorbidities. They describe the Ig responses to Mycobacterium tuberculosis of patients with chronic conditions, such as co-infection with HIV, diabetes or kidney diseases, where inflammation may facilitate tuberculosis re-activation. McLean et al. propose that inflammatory IgG profiles may be important biomarkers for the detection of progressive tuberculosis. More studies are needed to distinguish inflammatory antibody profiles that are the consequences of co-morbidities from those that contribute to the reactivation of tuberculosis.

Regarding severe viral infections, neutralizing antibodies hold great promise both for antibody-based therapeutic intervention and for vaccine design. This is illustrated by the paper by Gao et al., who applied next-generation sequencing (NGS) to probe the development of ZK2B, a potent E DIII-specific antibody protective against Zika virus (ZIKV), isolated from a convalescent individual. The NGS-derived, germline-like ZK2B10 somatic variants neutralized ZIKV and protected mice from ZIKV challenge, without cross-reactivity with Dengue virus. Site-directed mutagenesis identified residues essential to the functional maturation of ZK2B10. The repertoire and lineage features unveiled in this study should help elucidate the developmental process and protective potential of anti-ZIKV antibodies.

Gray et al. report on a rapidly progressive glomerulonephritis reproducing the auto-immune Goodpasture's disease (GP), caused by anti-glomerular basement membrane (GBM) antibodies developed after allogenic haematopoietic stem cell transplantation (HSCT). In GP, autoantibodies bind neoepitopes formed upon disruption of the structure of α345 NC1 hexamer, a critical domain of α345 collagen IV scaffolds. Upon hexamer disruption, α3 and α5 NC1 subunits become immunogens. Gray et al.'s is the first report of allo-incompatability and antigenic specificity in anti-GBM disease after allogenic HSCT. Both the patient and donor presented with the Goodpasture's susceptibility HLA-allele DRB1^*1501, and the patient's anti-GBM antibodies recognized the E_A epitope of the α3 NC1 monomer of collagen IV. Auto-antibody binding to native α345 NC1 hexamer was minimal, and there were no polymorphic differences between the donor's and recipient's collagen IV genes. The authors conclude that their patient's was a case of classical GP disease, the anti-GBM antibodies emerging post transplantation from the donor immune system. This hypothesis is supported by the finding that native a345 NC1 hexamer was not pathogenic in an animal model of GP disease, whereas immunization with dissociated hexamers induced glomerulonephritis (Gray et al.).

Another example is provided by systemic lupus erythematosus (SLE), where Zhang et al. investigated the role of IgG in spleen inflammation. They report that lupus IgGs are important pathological factors involved in the initiation of inflammation and further germinal center (GC) and plasma cell formation. Macrophages of the splenic marginal zone were dispensable for the GC response induced by lupus IgG, while red pulp macrophages were important for GC responses. Furthermore, lupus IgGs promoted inflammation and GC formation through the macrophage-mediated secretion of TNF-α. Interestingly, Syk inhibitor treatment suppressed the changes in the histopathology of the spleen induced by lupus IgGs.