1、Autoimmunity & Autoimmune Diseases,Section 11b,Introduction Immunologic Pathogenesis Typical Diseases Factors in development of autoimmune Treatment of Autoimmune Disease,Outline of the lecture,Concepts:,Autoimmunity: is defined as an acquired immune reactivity against self antigens. This response u

2、sually produces autoantibodies and autoreactive T cells.,Autoimmune disease,When autoimmune responses lead to tissue damage autoimmune disease occurs. The autoantibodies and autoreactive T cells against self antigens exist in all the individuals with autoimmune disease.,Classification,Autoimmune dis

3、eases can be broadly divided into organ-specific and systemic,Autoimmune diseases Affected organs Hashimotos thyroiditisthyroid Graves diseasethyroid Addisons diseaseadrenal glands Insulin-dependent diabetesislets mellitus (IDDM) Mutiple sclerosis (MS)brain, spine cord myasthenia gravis (MG)muscle A

4、utoimmune hemolytic anemiared blood cells (AIHA) thrombocytopenia purpura (ITP)platelets Goodpastures syndromebasement membranes of kidney and lungs,Organ-specific,Autoimmune diseases Affected organs Systemic lupusskin, joints, muscle, kidneys erythematosus (SLE)lungs, heart, nervous system Sjgrens

5、syndrome salivary gland, kidneys, thyroid Rheumatoid arthritis joints, lungs, heart Sclerodermaskin, joints, muscle, lungs, heart, kidney Polymyositisskeletal muscle,Systemic,Characteristics,The disease affects predominantly females Triggered in a genetically susceptible individual by an environment

6、al event the presence of autoantibodies and autoreactive T cells chronic and progressive observed in a form of autoimmune-overlap syndrome.,Introduction Immunologic Pathogenesis Factors in development of autoimmune Typical Diseases Treatment of Autoimmune Disease,Outline of the lecture,Causes of Dam

7、age in Autoimmune Diseases,Antibodies: Graves Disease, SLE T Cells: Polymyositis Complement: Paroxysmal Nocturnal Hemoglobinuria Phagocytes: Familial Mediterranean Fever,Autoimmune diseases may be associated with distinctive forms of tissue injury,In the vast majority of cases, autoimmune disease ar

8、e diagnosed on clinical grounds (that is, on the basis of findings on history and physical),Laboratory results reflecting the distinctive features of immune injury in each condition may also be seen,Introduction Immunologic Pathogenesis Factors in development of autoimmune Typical Diseases Treatment

9、 of Autoimmune Disease,Outline of the lecture,Factors in development of autoimmune,(1) Defects in immune tolerance (2) Autoantigens (3) Abnormal Immunoregulation (4) Abnormal Expression of Fas/FasL (5) Genetic Factors (6) Infections,The autoimmune regulator gene AIRE promotes the expression of some

10、tissue-specific antigens in thymic medullary cells, causing the deletion of immature thymocytes that can react to these antigens.,(1) Defects in immune tolerance,(2) Autoantigens 1) Molecular mimicry 2) Exposure of “hidden” self antigens 3) Epitope spreading,1) Molecular mimicry,some pathogens expre

11、ss protein or carbohydrate antigens that resemble host molecules. In such cases, these “self” antigens may cross-react with immunoglublin produced by a B cell clone that initially responded to a foreign antigen.,+ Poluclonal stimulant, e.g. Lipopolysacchride,Anti-heart Ab,Anti-lung Ab,Anti-kidney Ab

12、,Anti-insulin Ab,Some autoreactive B cells developed are anergized in peripheral tissue,Non-specific activation,2) Exposure of “hidden” self antigens,During the development of individual, the self antigens in immunologically privileged site, do not normally expose themselves to the outside of the ce

13、ll. They may actually act as “foreign” antigens if they are ever exposed to the cells exterior by injury.,Immunologically privileged sites:,Tissue grafts placed in Some sites in the body do not elicit immune response.,Damage to an Immunologically privileged sites can induce an autoimmune response,3)

14、 Epitope spreading,Autoimmune reaction usually initiated against one self antigen. The immune responses induced may injury tissues and result in the release and alterations of other tissue antigens which can activate lymphocytes specific for these other antigens, and exacerbate the disease. This phe

15、nomenon is called epitope spreading .,Epitope spreading in Pemphigus vulgaris,(3) Abnormal Immunoregulation,1) Polyclonal B cell or T cell activation 2) Abnormality of cosimulatory molecule expression 3) Th1 and Th2 unbanlance,Some microbes or their products activate lymphocytes independently of the

16、ir antigenic specificity. They can activate anergic B cells nonspecifically,1) Polyclonal B cell or T cell activation,The products of various microbes such as LPS , bacterial DNA and virus DNA can directly stimulate the immune cells to secret cytokines which can enhance the expression of MHC class I

17、I molecules, adhesion molecules, costimulatory molecules (B7, CD40L), and result in the breakdown of peripheral tolerance of selfreactive T cell.,2) Abnormality of cosimulatory molecule expression,Appropriate activation of nave T cells requires in addition to a ligand for the T cell receptor a secon

18、d interaction with CD28. This second signal is called costimulation. Under many conditions, dendritic cells provide this signal during a primary response.,Normal costimulation by signaling through CD28,3) Th1 and Th2 unbanlance,Generally, Th1 type cytokine involved in the responses in organ-specific

19、 autoimmune disease such as IDDM, multiple sclerosis and EAE, whereas Th2 type cytokine promote humoral autoimmune responses in systemic disease such as SLE and rheumatoid arthritis.,Th1 and Th2 subsets, through their secreted cytokines, inhibit each others effects and thus tend to prevent excessive

20、 immune responses. However, the immune responses to some microbes favors the activation of one Th cell subset over another, resulting in unbalanced cytokine production. This unbalance related to the development of autoimmune disease.,(4) Abnormal Expression of Fas/FasL,Fas protein is especially expr

21、essed on activated T and B cells. Ligation of Fas by Fas ligand which is present in the surface of killing cells leads to apoptotic cell death. In this way it functions to limit the extent of immune responses. Mutations that eliminate or inactivate the Fas protein lead to an accumulation of lymphocy

22、tes, especially T cells, and the production of large quantities of pathogenic autoantibodies.,Along with its role in cell killing, FasL is important in eliminating activated T cells,T cells,T cell,T cell,Fas deficiency leads to autoimmune lymphoproliferative syndrome,(5) Genetic Factors,Although eve

23、rybody is exposed to foreign antigens and many people get injuries, autoimmune diseases developed only in some individuals. Recent studies have formally established that autoimmune diseases usually have a complex association with multiple gene loci.,Associations of HLA alleles with diseases,Autoimmu

24、ne diseases HLA allele Relative risk,Ankylosing spondylitisB2790 Insulin-dependent diabetesDR3/DR425 mellitus (IDDM)heterozygote Goodpastures syndromeDR216 Pemphigus vulgarisDR414 Acute anterior uveitisB2710 Sjgrens syndrome Dw36 Systemic lupusDR35 - 6 erythematosus (SLE) Mutiple sclerosis (MS)DR25

25、Rheumatoid arthritis Dw4/DR44 - 5 Graves diseaseB8/DR33 - 4 Hashimotos thyroiditisDR53 - 4 myasthenia gravis (MG)DR32 - 3,(6) Infections,May lead to increased expression of costimulatory molecules and release of cytokines and chemokines by tissue APCs.,May produce peptides that are similar to self antigens (molecular mimicry),May also injure tissues and release antigens from immunologically privileged site