Autoimmunity, self-tolerance and immune homeostasis: from whole animal phenotypes to molecular pathways.
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Animals↗
Biomedical subjects
S Akkaraju
Publications and source records attributed to S Akkaraju.
How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis.
Therapy for transplant rejection, autoimmune disease and allergy must target mature lymphocytes that have escaped censoring during their development. FK506 and cyclosporin are immunosuppressants which block three antigen-receptor signalling pathways (NFAT, NFkappaB and JNK), through inhibition of calcineurin, and inhibit mature lymphocyte proliferation to antigen. Neither drug induces long-lived tolerance in vivo, however, necessitating chronic use with adverse side effects. Physiological mechanisms of peripheral tolerance to self-antigens provide an opportunity to emulate these processes pharmacologically. Here we use gene-expression arrays to provide a molecular explanation for the loss of mitogenic response in peripheral B-cell anergy, one aspect of immunological tolerance. Self-antigen induces a set of genes that includes negative regulators of signalling and transcription but not genes that promote proliferation. FK506 interferes with calcium-dependent components of the tolerance response and blocks an unexpectedly small fraction of the activation response. Many genes that were not previously connected to self-tolerance are revealed, and our findings provide a molecular fingerprint for the development of improved immunosuppressants that prevent lymphocyte activation without blocking peripheral tolerance.
Animals↗
Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells.
Graves' Disease results from the production of autoantibodies against receptors for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents the prototype for numerous autoimmune diseases caused by autoantibodies that bind to organ-specific cell membrane antigens. To study how humoral tolerance is normally maintained to organ-specific membrane antigens, transgenic mice were generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten, and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL autoantigen on thyroid cells did not trigger elimination or inactivation of circulating HEL-reactive B cells. These results provide evidence that tolerance is not actively acquired to organ-specific antigens in the preimmune B cell repertoire, underscoring the importance of maintaining tolerance to such antigens by other mechanisms. The role of an intact endothelial barrier in sequestering organ-specific antigens from circulating preimmune B cells is discussed.
Adoptive Transfer↗
A range of CD4 T cell tolerance: partial inactivation to organ-specific antigen allows nondestructive thyroiditis or insulitis.
T cell receptor (TCR) transgenic mice specific for hen egg lysozyme (HEL) were crossed with mice expressing HEL on the thyroid epithelium, on pancreatic islet beta cells, or systemically. Depending on the pattern of HEL expression, deletion of double-positive thymocytes ranged from minimal to complete, and peripheral CD4 cells exhibited graded reduction in TCR expression, in vitro responsiveness, and in vivo helper ability. CD4 cells were least tolerant in TCR/thyroid-HEL and TCR/islet-HEL mice, which developed an extensive lymphocytic thyroiditis or insulitis that nevertheless did not eliminate HEL-expressing endocrine cells. Autoreactive CD4 clones thus escape the thymus under a range of circumstances, retain sufficient function to initiate subclinical autoimmune inflammation when self-antigens are concentrated in the thyroid or pancreas, and may regulate progression of subclinical inflammation to destructive autoimmune disease.
Animals↗
C3d of complement as a molecular adjuvant: bridging innate and acquired immunity.
An optimal immune response should differentiate between harmful and innocuous antigens. Primitive systems of innate immunity, such as the complement system, may play a role in this distinction. When activated, the C3 component of complement attaches to potential antigens on microorganisms. To determine whether this alters acquired immune recognition, mice were immunized with a recombinant model antigen, hen egg lysozyme (HEL), fused to murine C3d. HEL bearing two and three copies of C3d was 1000- and 10,000-fold more immunogenic, respectively, than HEL alone. Thus, C3d is a molecular adjuvant of innate immunity that profoundly influences an acquired immune response.
Adjuvants, Immunologic↗
Self-tolerance checkpoints in B lymphocyte development.
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Animals↗
Binding of polycyclic and nitropolycyclic aromatic hydrocarbons to specific fractions of rat lung chromatin.
Carcinogen-induced damage to nuclear matrix DNA, the site of DNA replication and transcription, could have profound effects on gene regulation and mutation. 1,6-Dinitropyrene (1,6-DNP), 1-nitropyrene (1-NP), 6-nitrobenzo[a]pyrene (6-NBP), benzo[a]pyrene (BP) and benzo[a]pyrene diolepoxide (BPDE) were investigated for their abilities to bind to selected regions of DNA in rat lung cell nuclei. Following in vitro exposure to carcinogen, nuclei were fractionated into active chromatin (AC), nuclear matrix (NM) and bulk (low and high salt) chromatin fractions. At an equivalent molar concentration, the highest binding to unfractionated (total) DNA was obtained with BPDE, followed in order by BP, 1,6-DNP, 6-NBP and 1-NP. BPDE, a direct alkylating compound, was bound approximately 18 times higher than the other compounds. All compounds were bound to AC (mononucleosomal DNA approximately 185 bp) and to NM in greater amounts than to bulk DNA. The binding ratios (AC + NM)/(LS + HS) varied from 2 to 21, depending upon the compound. The selective binding to specific DNA regions did not appear to be significantly related to the structures of the parent compounds or to their inferred metabolites. Thus, it appears that selective binding to specific regions is a general phenomenon that is related to the open state of the chromatin structure.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗