Human T-cell responses to the stress protein alpha B-crystallin in multiple sclerosis (MS)-affected brain samples are dominant when compared to other myelin antigens. The establishment of the apparent autoimmune repertoire against this antigen has been suggested to involve cross-priming during viral infection. Yet, another possibility would be that determinant spreading during ocular inflammation could generate a response to alpha B-crystallin, since it is also a major component of the eye. In this study, we compared serum IgG, IgA and IgM repertoires against a range of eye lens-derived ocular antigens using sera from healthy control subjects and MS patients with or without uveitis. This comparison revealed that among ocular antigens, alpha B-crystallin is the dominant target antigen for serum autoantibodies in both MS patients and healthy controls. Uveitis generally did not affect the antibody reactivity profile. These data provide further support for the notion that a normal adult human immune system is selectively reactive to alpha B-crystallin and they indicate that this responsiveness is unlikely to result from determinant spreading following ocular inflammation.