Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE).However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE. IntroductionSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of antinuclear autoantibodies (1). SLE patients also frequently produce antilymphocyte antibodies of pathogenic potential that preferentially target CD45 (2, 3). These autoantibodies reflects a critical breakdown of B cell tolerance and the ensuing expansion of autoreactive B cells capable of inducing disease through both antibody-dependent and antibody-independent mechanisms (4). Regrettably, understanding how tolerance is abrogated in SLE has been hampered by experimental limitations in identifying relevant autoreactive B cells.We have proposed that B cells bearing the 9G4 idiotype (9G4 B cells) represent a useful system to study B cell tolerance in SLE, since the expression of this idiotype (which identifies antibodies encoded by the VH4.34 heavy chain) is synonymous with autoreactivity against N-acetyllactosamine (NAL) determinants expressed by the iI blood group antigen and other self glycoproteins including CD45 (3,5,6). Moreover, the 9G4-determined autoreactivity is censored in normal subjects but greatly and specifically expanded in patients with active SLE. Thus, while 9G4 B cells represent 5-10% of normal naive B cells, serum 9G4 antibodies are scarce in normal sera (3, 7). In contrast, these autoantibodies are abundant in patients with active SLE, representing 10-45% of total serum IgG (3,8,9). Importantly, 9G4 antibodies represent the vast majority of anti-B cell CD45 antibodies and a significant fraction of anti-native double-stranded DNA (anti-dsDNA) antibodies, carry a disease specificity of 95%, and correlate with disease activity and organ involvement (3,(8)(9)(10). These observations support the con-

Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38+ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.

Emergency room personnel successfully manage the majority of patients with foreign bodies of the external auditory canal. For patients with firm, rounded objects, direct otolaryngology consultation without further manipulation should be strongly considered. Patients who have had previous removal attempts should not undergo further manipulation in the emergency department but rather should be referred directly to an otolaryngologist.

ABSTRACT

Many institutions require that tracheotomies be performed in the operating room. Movement of critically ill patients dependent on multiple life support systems is technically difficult, labor intensive, and potentially dangerous for the patients. Between 1983 and 1992, 1088 tracheotomies were performed on patients ages 1 week to 94 years at the University of Rochester affiliated hospitals on critically ill patients as isolated procedures. The procedure was performed in the Intensive Care Units (ICU) on 996 patients, (92.9%), whereas 92 patients (7.1%) had tracheotomies in the operating room (OR1). An additional 346 tracheotomies took place in the operating room in conjunction with other head and neck procedures (OR2). Incidence of perioperative bleeding (within 48 hours) was 2.3% in the ICU group, 2.1% in the ORI group, and 2.0% in the OR2 group. Incidence of stomal infection was also similar among the three groups at 1.8%, 2.1%, and 1.5%, respectively. Tube dislodgement in all groups was a complication. No statistical differences were noted among the three groups (ICU, OR1, OR2) at the p < 0.01 level. Criteria for performing the tracheotomy in the ICU are delineated and discussed.