Antibody specificity of the human monoclonal immunoglobulins: the elusive target antigen

Human monoclonal immunoglobulins (HMIGs) are encountered in different clinical conditions mainly including (auto)immune disorders, immunodeficiencies and B-cell malignancies. However, in some cases no associated-disease is evidenced and they are considered as "idiopathic". Their incidence increases with age. The factors involved in the emergence and regulation of the growth and differentiation of B-cell clones secreting HMIGs are unknown but might implicate T-cell dysfunction. One approach to elucidate the origin of such B-cell clones is to identify the putative target antigen. For this reason, we have reviewed the antibody (Ab) specificity of 8439 HMIGs described in the literature, the data coming from 24 systematic screenings. Very few HMIGs present anti-hapten activity (1%) or specificity for foreign antigens (0.3%). On the other hand, the data quoted strongly document an auto-Ab (Ab1 type) activity in a large percentage of the HMIGs, mainly of the IgM type (at least greater than 30%), with properties similar to those of naturally occurring auto-Abs. Furthermore, there is some evidence that HMIGs may express anti-idiotypic activity (Ab2) to human (auto)-Abs. Finally, many of the HMIGs which are devoid of detectable auto-Ab activity (i.e., mainly IgG, IgA) share cross-reactive idiotypes with natural auto-Abs. It may be speculated that some of these HMIGs actually represent either Ab of the Ab3 type i.e., anti-anti-idiotypic Ab to auto-Abs or Ab which have varied sufficiently to loose auto-or-foreign-antigen-binding activity but maintaining idiotype. As a whole, these data demonstrate that many HMIGs are the secretory products of the auto-reactive B-cell clones which produce natural auto-Abs (including anti-idiotypic and anti-anti-idiotypic Abs) and which are characterized by a very high degree of idiotypic connection. Since HMIGs arise from such clones, it may be postulated that the emergence of HMIGs might be due to a dysfunction of the system that normally regulates such an Ab production.