This application proposes a continuation of studies examining the handling of self proteins by antigen presenting cells (APC). These studies are geared to examine the issue of central tolerance from the perspective of the processing and presentation of self molecules. During the past two years, Dr. Allen and coworkers have developed a model to study the processing and presentation of the self protein hemoglobin (Hb). Using this system they obtained direct proof that self hemoglobin/Ia complexes are expressed constitutively in vivo. This demonstration of the inability of Ia molecules to distinguish between foreign and self antigens has tremendous implications for the processes of self tolerance and autoimmunity. These workers now propose to continue studies using the hemoglobin system as well as develop other new antigen systems. Initially they will examine non-lymphoid organ APC for the expression of the Hb/Ia complexes. The investigators will then examine all of the different cell types, both lymphoid and non-lymphoid, shown to express the Hb/Ia complexes for their ability to express co-stimulator molecules which are required for T cell activation. It is then proposed to develop three new antigen systems with which the processing and potential presentation of other self proteins will be examined. These antigens are: 1) a sperm-specific heat shock protein, HSP70.1, which is developmentally expressed during puberty; 2) glial fibrillary acid protein, a protein only expressed in astrocytes in the brain and is thus compartmentalized; and 3) B-galactosidase, a protein which is contained in lysosomes and circulates in low levels. By studying these three different antigen systems the investigators will be able to further understand how the immune system copes with various self proteins. It is also proposed to ascertain the molecular basis of the non-responsiveness of B10.BR mice to the peptide determinant Hbb(67-76) which is due to a non-gene. This non-responsiveness could be due to a deletion of a particular VB as has been observed for Mls, or a self protein which has a cross reactive determinant, and the process of self tolerance to this protein eliminates the reactive T cells to Hbb(67-76). Finally, it is proposed to generate monoclonal antibodies against peptide antigens which will recognize these antigens only when they are bound to an Ia molecule. From these proposed studies one could gain a better understanding of the handling of self proteins by antigen presenting cells, the results of which may aid in the design of better vaccines and the prevention of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024157-05
Application #
3136910
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Milam, Ashley A Viehmann; Bartleson, Juliet M; Donermeyer, David L et al. (2018) Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response. J Immunol 200:3429-3437
Ransdell, Joseph L; Dranoff, Edward; Lau, Brandon et al. (2017) Loss of Nav?4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance. Cell Rep 19:532-544
Viehmann Milam, Ashley A; Allen, Paul M (2017) The TCR Takes Some Immune Responsibility. Immunity 47:803-804
Hong, Jinsung; Persaud, Stephen P; Horvath, Stephen et al. (2015) Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells. J Immunol 195:3557-64
Rodriguez, Stephanie N; Jiang, Meizi; Bujo, Hideaki et al. (2015) Self-pMHCII complexes are variably expressed in the thymus and periphery independent of mRNA expression but dependent on the activation state of the APCs. Mol Immunol 63:428-36
Klein, Ludger; Kyewski, Bruno; Allen, Paul M et al. (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14:377-91
Ni, Peggy P; Solomon, Benjamin; Hsieh, Chyi-Song et al. (2014) The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires. J Immunol 193:1778-86
Persaud, Stephen P; Parker, Chelsea R; Lo, Wan-Lin et al. (2014) Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. Nat Immunol 15:266-74
Chou, Chun; Pinto, Amelia K; Curtis, Jonathan D et al. (2014) c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nat Immunol 15:884-93
Ni, Peggy P; Wang, Yaming; Allen, Paul M (2014) Both positive and negative effects on immune responses by expression of a second class II MHC molecule. Mol Immunol 62:199-208

Showing the most recent 10 out of 57 publications