Regulatory Mechanisms in the Immune Response to Cell-surface Antigens

Intrastructural help in diversification of humoral autoimmune responses

“…It was later shown, first by Lake and Mitchison and later by others, that this requirement may be different for proteins that are parts of a macromolecular structure such as a cell or a virus [24]; B and T cell epitopes need physical association within intact complexes, but not necessarily a covalent one. As one example, Milich and colleagues demonstrated that antibodies to the hepatitis B virus surface protein can develop in mice that were first primed with an immunodominant peptide of the core protein and then challenged with sub-immunogenic doses of intact hepatitis virions [25].…”

Self antigens and epitope spreading in systemic autoimmunity

“…While early studies of conventional immune responses to soluble immunogens demonstrated a requirement for covalent association of both T and B cell epitopes on the same antigen (48,49), Lake and Mitchison noted in 1976 that these epitopes could also reside on different molecules on the surface of the same cell (50). Such T-dependent B cell help was designated intermolecular or intrastructural, to distinguish it from intramolecular T cell help for covalently linked epitopes, and it relied upon the notion that on a particulate antigen, recognition of a distant, noncovalently linked epitope by T helper cells could mediate an antibody response.…”

Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit

“…For example, anti-Sm antibodies recognizing the B'/B and D proteins of U1 small nuclear ribonucleoproteins (snRNPs) virtually always are accompanied by anti-nRNP antibodies recognizing the U1-A, U1-C, and U1-70K proteins [2,3]. 'Linked sets' of autoantibodies may be a consequence of B cell surface immunoglobulin-mediated uptake and processing of antigenic particles [4], since T cells responsive to a peptide derived from one component of a particle may provide 'intermolecular-intrastructural' help to B cells producing antibodies to other components [5][6][7]. The mechanisms responsible for linked autoantibody sets are incompletely understood, however.…”