Lewis rats immunized with Peptide M (an oligopeptide epitope of the S-antigen protein) developed experimental autoimmune uveoretinitis (EAU) and experimental autoimmune pinealitis (EAP). Temporal changes in mononuclear infiltrate to the pineal gland were quantitated by computer image analysis of sections immunostained with monoclonal antibodies to specific mononuclear populations. T helper/inducer cells (W3/25+) and monocyte/macrophages (OX-42+) were elevated during the early phases of inflammation (day 15) while cytotoxic/suppressor T cells (OX-8+) were elevated at days 15 and 21. Expression of MHC class II (OX-6) was markedly enhanced on pineal glia, but was not present on vascular endothelia during EAP. Ultrastructurally, many capillaries exhibited thickenings of the endothelia and basal lamina. EAP had little effect on the fine structure of pinealocytes and glia and there was little evidence of cellular destruction by day 21, in contrast to the extensive retinal destruction resulting from EAU. These findings suggest fundamental differences between EAU and EAP related to mechanisms of antigen processing/recognition in autoimmune diseases. Our study further indicates the importance of EAP as a model to investigate neuroendocrine-immune interactions.