The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.In mice, the primary antibody response against phosphorylcholine (PC), the dominant hapten on the pneumococcal cell wall, demonstrates remarkable restriction of heavy and light chain variable region (VH and VL, respectively) gene usage, with the dominant antibody expressing the T15 idiotype (1). We have previously demonstrated in an in vitro system that a single amino acid substitution in a T15+ anti-PC antibody, S107, results in an antibody, U4, that has diminished recognition of PC and instead binds double-stranded DNA

To evaluate the spectrum and treatment of posterior segment complications in eyes that had undergone successful keratoprosthesis (KPro) placement and to determine whether transeyelid vitrectomy techniques could be effectively used in eyes otherwise vulnerable to surface exposure. Design: In the last 10 years, 110 patients received a Dohlman-Doane KPro at the Massachusetts Eye and Ear Infirmary, Boston. We evaluated 22 eyes in 18 patients that required subsequent vitreoretinal surgery to treat posterior segment complications. One surgeon using modified vitreoretinal techniques, as described below, performed all vitreoretinal procedures. Results: The posterior segment complications included 6 cases of retro-KPro membranes, 13 cases of retinal detachments, and 5 cases of isolated vitreous opacity. All 6 retro-KPro membranes were effectively removed by vitrectomy without significant complication and 3 of these patients enjoyed improvement of visual acuity of at least 5 Snellen lines. Of 13 cases of retinal detachment, 6 patients had some improvement in visual acuity, 5 showed no appreciable change, and 2 had some decline in the final visual acuity. In all 5 cases of isolated vitreous opacity, the media was effectively cleared with pars plana vitrectomy. Three patients enjoyed improvement of visual acuity of at least 3 Snellen lines. Four cases of transeyelid vitrectomy were attempted and anatomical success was achieved in all 4 and vision improved in 3 of these patients. No special surgical complications were encountered in any of the 22 eyes as a result of these modified surgical techniques. Main Outcome Measures: Best preoperative and postoperative visual acuity and anatomical success were evaluated in relation to the preoperative posterior segment complication. Conclusions: Modified vitreoretinal surgical techniques can be effectively and safely used to treat posterior segment complications in patients with KPro devices. Retro-KPro membranes and other vitreous opacities were the most amenable to treatment. Retinal complications posed a special challenge. However, all of these cases highlight that modified vitrectomy techniques can be used in eyes with permanent KPro devices. These techniques can be performed without additional risk to the eye. Additionally, we demonstrated that transeyelid vitrectomy techniques could be used effectively to manage complications in eyes with severe ocular surface disease without undue exposure of vulnerable tissues.

The skin is a classic target tissue for thyroid hormone action. Although the histology of skin in hypothyroid states is well documented, the literature contains little assessment of skin in thyrotoxic states. In light of the paucity of information on skin under the influence of excess thyroid hormone, we investigated the direct effect of thyroid hormone on skin. Triiodothyronine (T3) was applied topically daily in liposomes to SKH-1 hairless mice for 7 days and to CD rats for 2 weeks. There was a dose-dependent increase in epidermal proliferation, dermal thickening, and hair growth in T3-treated animals. Mice that received 3.8 microg of T3 had 42% more hairs per millimeter than controls (p < 0.01), hair length that was 1,180% longer (p < 0.001), 49% greater epidermal 3H-thymidine incorporation (p < 0.01), and 80% more 5-bromo-2'-deoxyuridine (BrdU) stained cells (p < 0.05). Rats receiving 12.8 microg T3 had 48% greater dermal thickness than controls (p < 0.001), 26% greater epidermal thickness (p < 0.001), 85% more hairs per millimeter (p < 0.005), and 130% greater 3H-thymidine incorporation into the epidermis (p < 0.01). Thus, topically applied thyroid hormone has dramatic effects on both skin and hair growth. These observations offer a new strategy for developing thyroid hormone and its analogues for treating disorders of skin and hair growth.

Cystoid macular edema (CME) following cataract surgery has been recognized for over 50 years as an important cause of suboptimal post-operative vision. The incidence of CME varies widely, but is likely in the range of 1-2% using modern cataract extraction techniques. The diagnosis of CME can generally be made on clinical examination with evidence of perifoveal cystic spaces and can be confirmed with use of fluorescein angiography to document the classic petaloid pattern of leakage mainly into the outer retina. Leak from perifoveal vessels is induced by inflammatory mediators and results in intraretinal fluid accumulation and corresponding decrease in retinal function. The risk factors most associated with CME; rupture of posterior capsule, vitreous loss, iris incarceration, use of iris fixated lenses, active uveitis and diabetes, may all increase the potency of these mediators and exacerbate post-operative CME. The treatment of CME remains controversial but generally starts with conservative observation in isolated angiographic cases and progresses through topical non-steroidal anti-inflammatory agents (NSAIDs), topical steroids, peri-ocular steroids, systemic steroids and surgical intervention in refractory cases. Even more controversial is the role of NSAID prophylaxis peri-operatively in preventing clinical CME. Though the data is tantalizing in the short term, there is little to support the long-term benefit of such prophylaxis with respect to visual outcomes.