No abstract

We have examined whether an association exists between specific Ia antigen genes and Ir genes which are encoded within the same haplotype. Functionally monospecific sera to the Ia antigens of the guinea pig MHC were selective in their ability to inhibit antigen-specific T-cell proliferation and we were thus able to demonstrate an association between individual Ia specificities and specific Ir genes. The results of these studies in inbred animals were confirmed by examining the association of Ir genes and Ia antigens in the outbred guinea pig population. Of great interest was the observation that antisera made against cross-reactive Ia antigens of strains lacking specific Ir genes would still inhibit immune responses of strains possessing the Ir gene, if the Ir gene was associated with that Ia antigen in the responder strain.

The Ia antigens of the guinea pig have been shown to play a central role in the regulation of the immune response. We have previously partially characterized the chemical structure of these antigens. In this communication, we further characterize the structure of the five Ia antigens already described, as well as two new Ia antigens. Evidence is presented which shows that these seven Ia antigens can be organized into three distinct groups, each with a characteristic structure. The Ia.2 determinant of strain 2 and the Ia.3 and Ia.5 determinants of strain 13 animals are found on molecules composed of a 25,000 dalton chain and a 33,000 dalton chain in noncovalent association, or else are individually expressed on nonlinked 33,000 and 25,000 dalton molecules. The Ia.4 and Ia.5 determinants of strain 2 and the Ia.7 determinant of strain 13 are borne on 58,000 dalton molecules in which two chains are linked by disulfide bonds. The Ia.1 and Ia.6 determinants of strain 13 are found on a molecule of 26,000-27,000 daltons. Ia.6 of strain 2 has yet to be definitively assigned. Furthermore, in strain 13 animals the Ia.3 and Ia.5 determinants are borne on the same molecule, as are the Ia.1 and Ia.6 determinants. In strain 2 animals, the Ia.4 and Ia.5 determinants are found on the same molecule. On the basis of chemical structure, we have divided the guinea pig I region into three subregions. The accompanying paper presents evidence of associations between particular Ia genes and Ir genes.

The recent demonstrations that migration inhibitory factor (MIF) (1-4), chemotactic factor (5), mitogenic factor (6, 7), and lymphotoxin (8) can be produced by B as well as T lymphocytes have raised serious doubts about the validity of in vitro assays for cell-mediated immunity as indices of T-cell function . Yet there are a number of human disease states in which the biological significance of the in vitro production of mediators by B cells may be called into question. For example, lepromatous leprosy and chronic mucocutaneous candidiasis are characterized by specific functional T-cell deficiency and failure of macrophage killing of ingested organisms despite high levels of circulating antibodies to the offending parasite . If B cells are capable of producing the mediators of delayedtype hypersensitivity, why are they ineffective at initiating macrophage activation in these diseases?We have pursued the question whether B cells can be activated by antigen to produce MIF in a model that excludes participation of T cells by virtue of an immune response (Ir) gene restriction . Strain 2 guinea pigs respond to immunization with the 2,4-dinitrophenyl (DNP) derivative of poly-L-lysine (PLL) with the production of antibody and delayed-type hypersensitivity ; strain 13 animals are nonresponders (9) . However, strain 13 animals can respond to DNP-PLL when the molecule is complexed to an immunogenic carrier, such as ovalbumin (10). In this situation, anti-DNP antibodies are produced, but delayed-type cutaneous reactivity and blastogenesis to DNP-PLL are absent (11), indicating an absence of T cells capable of responding to DNP-PLL . This system allows us to test directly the question whether MIF can be produced by interaction of antigen with primed B cells in the absence of competent T cells. Materials and MethodsPLL hydrobromide (mol wt 90,000) was obtained from New England Nuclear, Boston, Mass . Guinea pig albumin (GPA) was prepared from strain 13 guinea pig serum by the method of Schwert (12) . DNP32 -PLL and DNP2u-GPA were prepared as previously described (13) . The subscripts refer to the average number of DNP groups per molecule . Twice recrystallized hen ovalbumin (Ova) was obtained from Miles Laboratories Inc., Elkhart, Ind.Preparation ofDNP-PLL-Ova Complexes . Equimolar amounts of Ova were added to DNP-PLL in 0.075 M NaCI dropwise with the formation of a precipitate.

No abstract