Seminars in Immunology 27 (2015) 138–143 Contents lists available at ScienceDirect Seminars in Immunology j our na l ho me pa ge: www.elsevier.com/locate/ysmim Review Virus-induced preferential antibody gene-usage and its importance in humoral autoimmunity Francesca Cappelletti, Nicola Clementi, Nicasio Mancini, Massimo Clementi, Roberto Burioni * Laboratory of Microbiology and Virology, Università “Vita-Salute” San Raffaele, Milano, Italy a r t i c l e i n f o Article history: Received 12 November 2014 Accepted 13 March 2015 Keywords: Antibody germline Antibody gene-usage Pathogen-driven gene-usage Humoral autoimmunity Catalytic antibodies a b s t r a c t It is known that even the adaptive components of the immune system are based on genetic traits common to all individuals, and that diversity is shaped by the lifelong contacts with different non-self antigens, including those found on infectious pathogens. Besides the individual differences, some of these common traits may be more prone to react against a given antigen, and this may be exploited by the infectious pathogens. Indeed, viral infections can deregulate immune response by subverting antibody (Ab) gene usage, leading to the overexpression of specific Ab subfamilies. This overexpression often results in a protective antiviral response but, in some cases, also correlates with a higher likelihood of developing humoral autoimmune disorders. These aspects of virus-induced autoimmunity have never been thor- oughly reviewed, and this is the main purpose of this review. An accurate examination of virus specific Ab subfamilies elicited during infections may help further characterize the complex interplay between viruses and the humoral immune response, and be useful in the design of future monoclonal antibody (mAb)-based anti-infective prophylactic and therapeutic strategies. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction The correlation between viral infections and the development of several autoimmune disorders has been known, or at least sus- pected, for a long time. However, in most cases, the fine molecular mechanisms of this interplay have not been clarified yet, especially when the humoral response is involved. The main purpose of this mini-review is to give some practical examples of virus–host inter- actions leading to the selective elicitation of antibody subfamilies prone to autoimmune reactivity. More in details, we will describe the possible autoimmune effect of the hyper-production of VH1- 69 and VH4-34 antibody subfamilies elicited during hepatitis C virus (HCV), human immunodeficiency virus (HIV) and influenza viruses infection, and during Epstein–Barr virus (EBV) reactivation, respectively. * Corresponding author at: Laboratory of Microbiology and Virology, Università “Vita-Salute” San Raffaele, Via Olgettina 58, 20132 Milano, Italy. Tel.: +39 02 2643 3023; fax: +39 02 2643 4288. E-mail address: burioni.roberto@hsr.it (R. Burioni). 2. Antibodies preferential gene-usage during viral infections: the example of VH1-69 germline The great variability of antibody repertoire in a single individ- ual and among different subjects is in all cases based on the use of a definite number of chromosomally encoded genes, known as antibody germlines [1]. As a result, the antigen-specific somatic hypermutation of only few germline genes allows the production of a virtually infinite number of different immunoglobulins [2–4]. This is particularly evident in cases when different individuals pro- duce different immunoglobulins against the same pathogen, but all originating from a single antibody germline gene. Under this perspective, a clear example of a virus-induced anti- body subfamily overexpression is the elicitation of the VH1-69 germline during HCV and HIV infections [5,6]. Usually, VH1-69 germline antibodies are not overrepresented in healthy individuals and are expressed only by 2% of peripheral blood B cells, accord- ingly to a random use of the total repertoire of antibody variable heavy chain (VH) gene regions [7]. Under a structural point of view, VH are composed of framework (FR) and the more variable complementarity determining regions (CDR), the latter being more important in the binding to the antigen (Fig. 1). On the contrary, in the case of VH1-69, it is largely accepted that the framework regions retain per se the ability of binding to hydrophobic regions, http://dx.doi.org/10.1016/j.smim.2015.03.008 1044-5323/© 2015 Elsevier Ltd. All rights reserved.