CTLA-4 in Autoimmune Disease (Medical Intelligence Unit Series) Book

	Preface	ix
1.	Autoimune Disorders--A Common Link?	1
	The Immune System in Autoimmunity	1
	Autoimmune Diseases	2
	Genetics of Autoimmune Diseases	4
	Do We Know the Genes?	5
	The Human Leukocyte Antigen (HLA) System	5
	Other Genes	6
	Immunomodulation as Treatment of Autoimmune Diseases	6
2.	CTLA-4: Its Role in the Immune Response	9
	Introduction	9
	CTLA-4 Characteristics and Properties	9
	Regulation and Localization of CTLA-4 Expression	10
	Function of CTLA-4 in vitro	11
	CTLA-4-Deficient Mice	12
	Effects of CTLA-4 in Different T Cell Subsets and Stages of T Cell Differentiation	12
	Signaling Properties of CTLA-4	13
	Inhibitory Effects of CTLA-4 in Experimental Models of Disease	16
	Role of CTLA-4 in Central and Peripheral Tolerance	17
	Role of CTLA-4 in Autoimmune Diseases in Humans	19
	Conclusion	19
3.	CTLA-4 in Systemic Lupus Erythematosus	25
	Introduction	25
	CLTA-4 in the Pathogenesis of Lupus	26
	Blockage of Costimulatory Signals in Murine Models of Human SLE	27
	CTLA4Ig Treatment in Murine Lupus Nephritis	28
4.	CTLA-4 in Rheumatoid Arthritis	35
	Introduction	35
	CTLA-4 Polymorphism in Patients with RA	36
	Increased Expression of CTL-4 on RA Synovial T Cells	38
	Altered Expression of the CTLA-4 Counter-Receptors, CD80, and CD86, in Patients with RA	38
	Potential Pathogenetic Role of CTLA-4 in T Cell-Mediated Interactions in RA	40
	RA as a Potential Target of CTLA-4-Related Therapeutic Interventions--Future Directions	41
5.	CTLA-4 in Autoimmune Thyroid Disease and Vitiligo	45
	Introduction	45
	Graves' Disease	46
	Thyroid-Associated Ophthalmopathy	46
	Autoimmune Hypothyroidism	47
	Postpartum Thyroiditis	48
	Vitiligo	49
	Conclusion	51
6.	CTLA-4 in Myasthenia Gravis	55
	Introduction	55
	Distribution of Ctla-4 (AT)n Polymorphism in Patients with MG	56
	Ctla-4 (AT)n Is Associated with Thymoma	56
	Different Distribution of Ctla-4 (AT)n in MG Patients Stratified by Genetic Markers on Chromosomes 2 and 6	57
	Ctla-4 (AT)n Is Associated to ADCC	58
	Functional Correlates to the Ctla-4 (AT)n	59
	Conclusions	59
7.	CTLA-4 in Multiple Sclerosis	63
	Introduction	63
	Receptors and Ligands in the B7:CD28/CTLA-4 Costimulatory Pathway	63
	B7:CD28/CTLA-4 Pathway and the Induction of EAE	64
	B7:CD28 Costimulation in the Effector Phase of Autoimmune Disease	65
	The Role of B7:CTLA-4 Interactions in EAE	65
	New Pathways within the B7:CD28 Superfamily and EAE	67
	Concluding Remarks	68
8.	CTLA-4 in Addison's Disease	71
	Introduction	71
	Addison's Disease as Part of a Polyglandular Syndrome	71
	The CTLA4 Gene and Addison's Disease	72
	Subjects	72
	Methods	73
	Single Strand Conformation Polymorphism (SSCP) Analysis of CTLA4 Polymorphisms	73
	Typing for HLA DQA1 and DQB1 Alleles	73
	Statistical Methods	73
	CTLA4 Exon 1 Polymorphisms in Patients with Addison's Disease	74
	CTLA4 Exon 1 Polymorphisms in Patients with Autoimmune Hypothyroidism (Hashimoto's Thyroiditis)	74
	Discussion	74
	CTLA4 Polymorphisms in Addison's Disease from Other European Countries	76
	Findings of CTLA4 Variants in Type 1 Diabetes and Ramifications for Addison's Disease and Type 2 Diabetes	77
9.	CTLA-4 in Type 1 Diabetes Mellitus	79
	Introduction	79
	The Discovery of the CTLA-4 Association with Type 1 Diabetes	80
	Genetic Studies on CTLA-4 and Human Type 1 Diabetes	82
	Role of CTLA-4 in Human Type 1 Diabetes	83
	Genetic Studies in Animals	85
	Functional Studies in Mice	86
	Conclusion	87
10.	CTLA-4: Its Role in Transplant Tolerance and Rejection	93
	Introduction	93
	The Role of CTLA-4 in the Allogeneic Immune Response	94
	The Role of CTLA-4 Negative-Signaling in Long-Term Engraftment Induced by Tolerogenic Treatment Strategies	94
	Utilization of the CTLA-4 Pathway for Therapeutic Intervention in Transplantation	96
	The Role of CTLA-4 and Regulatory Cells in Induction and Maintenance of Engraftment	98
	Index	101