Autoantibodies is among the most striking evidence of a break in immune tolerance and they occur in most systemic autoimmune diseases. Whereas some autoantibodies are pathogenic and can be used to classify specific autoimmune diseases, autoreactivity also occurs in a variety of other circumstances, such as during infections, immunizations and following certain traumatic accidents. The precise cellular and/or molecular mechanisms resulting in the development of pathogenic vs nonpathogenic antibodies remains elusive. Although pathogenic autoantibodies are usually of post-switched Ig classes and carry somatically mutated IgV genes as indications of extensive T cell help, it has not been clearly shown that the production of these autoantibodies has been initiated by specific autoantigens or whether they occur as a result of abnormalities in the control of B cell responses to exogenous antigens. Very recent evidence from B cell depletion studies using rituximab (anti-CD20) indicate that clinical improvement, decline in circulating B cells and decrease of antibody titres can all occur but do not correlate with each other, and therefore autoantibodies as products of differentiated plasma cells may not be the essential pathogenic element in a number of autoimmune disease. However, intrinsic abnormalities of B cell function (Table 1) and/or their interaction with other immune cells appear to be of central importance in these diseases. Here we discuss mechanisms, including extrinsic and intrinsic influences on B cell function and potential candidate molecules that could drive B cell dysfunction in autoimmune disease and might, therefore, serve as targets of therapeutic intervention.

The importance of precise immune regulation becomes evident when the characteristics of some immune deficiency and autoimmune disorders are compared. In the humoral immune system, B cells and their descendants, plasma cells, produce protective antibodies and thereby maintain the unique serological memory and a considerable part of cellular memory. Besides these well-known activities, a number of other immune functions of B cells have been identified in the last several years (Table 2), which need consideration not only for understanding their function in health but also under disease conditions. It is apparent that disturbances in the tightly regulated circuits of these cellular components with their products can lead to clinically important disorders. Analyses of inherited immune deficiencies have provided insights

Table 1 Potential B cell abnormalities leading to autoimmunity a. V(D)J recombination b. Entry of B cells into the immune repertoire c. Survival of B cells by altered apoptosis d. Selection e. Somatic hypermutation f. Receptor editing/revision g. Differentiation of plasma cells h. Extrinsic

- T cells, cytokines, APC, autoantigens i. Altered activation threshold

Table 2 Immune functions of B cells

1. Precursors of (auto)antibody-secreting plasma cells

2. Essential functions of B cells in regulating immune responses i. Antigen-presenting cells ii. Differentiation of follicular dendritic cells in secondary lymphoid organs iii. Essential role in lymphoid organogenesis as well as in the initiation and regulation of T and B cell responses iv. Development of effective lymphoid architecture (antigen-presenting M cells)

v. Activated B cells express costimulatory molecules and may differentiate into polarized cytokine-producing effector cells that can be essential for the evolution of T effector cells vi. Differentiation of T effector cells vii. Immunoregulatory functions by IL-10 positive B cells viii. Cytokine production by activated B cells may influence the function of antigen-presenting dendritic cells into the function of certain surface receptors as well as extracellular and subcellular components. For example, it is well accepted that inherited deficiencies of the complement system are associated with an increased incidence of SLE, glomerulonephritis, and vasculitis. Several antibody deficiencies are also associated with autoimmune disease. In this regard, autoimmune cytope-nias are commonly observed in individuals with selective IgA deficiency and common variable immune deficiency. Polyarthritis can also be seen in patients with X-linked agammaglobulinemia. Combined cellular and antibody deficiencies, such as Wiskott-Aldrich syndrome also carry an increased risk for juvenile rheumatoid arthritis and autoimmune hemolytic anemia. Recent advances in understanding the subcellular regulation of immune activation may allow further insights into the mechanisms of autoimmunity.

Abnormalities in certain receptors involved in B cell differentiation and Ig production can also be involved in a broad variety of disorders ranging between immune deficiency and autoimmunity. In this regard, loss of function mutations of the inducible co-stimulatory molecule (ICOS) expressed on T cells has been shown to be involved in adult onset common variable deficiency (Grimbacher et al. 2003). On the other hand, in murine (Iwai et al. 2003) as well in human lupus (Hutloff et al. 2004; Iwai et al. 2003), overexpression of ICOS on T cells and an overall downmodulation of ICOS-L on B cells (Hutloff et al. 2004; Iwai et al. 2003) were identified. Similarly, CD40L and Fas mutations have also been shown to be critically involved in both immunodeficiency as well as autoimmunity. Thus, loss of precise regulatory influences stabilizing B cell homeostasis can result in autoimmunity or immune deficiency or sometimes both.

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