Autoimmunity and B-cell malignancies

There is evidence indicating that autoreactive B cells constitute a substantial part of the B-cell repertoire. This autoreactive repertoire secrete the so called natural autoantibodies characterized by their broad reactivity mainly directed against very well conserved public epitopes. They fulfill the definition of an autoantibody since they are self-reactive, but they are not self-specific. As yet, NAA directed against determinants of polymorphism have not been reported. Their germinal origin is suggested by their early appearance during ontogeny, their expression of cross-reactive idiotopes and structural studies of their sequence. As for the physiological role of the repertoire, we can assume that it may play a major role as a first barrier of defense. It is presently unknown whether these polyreactive B cells could constitute a pre-immune template which through an antigen driven process may be involved in the production of immune high affinity antibodies. This autoreactive B cell repertoire frequently undergoes malignant transformation, although there is controversy concerning the reasons accounting for this. It has been postulated that the continuous challenge of this autoreactive repertoire by self-antigens could create propitious conditions for malignant transformation to occur. However, it can be alternatively postulated, that overexpression of certain genes reflect what happens during ontogeny, since V genes expression is a developmentally regulated phenomenon and not all V genes are expressed during fetal life. Some of the genes that are recurrently expressed by these malignancies are also over-expressed in fetal repertoires and even in the adult normal B cell repertoire. We do not know whether it is the challenge by self-antigens or whether alternatively this over-expression simply reflects what happens with the fetal repertoire which could have selective advantages for malignization.