Cellular Pathology of immunological disorders

Transcription

1 Cellular Pathology of immunological disorders SCBM344 Cellular and Molecular Pathology Witchuda Payuhakrit, Ph.D (Pathobiology)

2 Objectives Describe the etiology of immunological disorders Explain the mechanism of immunological disorders Hypersensitivity 2

3 Immunological disorders Immunological disorders are diseases or conditions caused by a dysfunction of the immune system 1. Hypersensitivity reactions 2. Deficiency state 3

4 Hypersensitivity Disorders caused by an abnormally active immune system Individuals who have been previously exposed to an antigen are said to be sensitized Repeat exposures to the same antigen trigger a pathologic reaction; such reactions are described as hypersensitivity Exogenous and endogenous may elicit hypersensitivity 4

5 Hypersensitivity 4 types of hypersensitivity reactions Immediate hypersensitivity Antibody- mediated hypersensitivity Immune complex hypersensitivity Cell- mediated hypersensitivity 5

6 Hypersensitivity The development of hypersensitivity disease is often associated with the inherence of particular susceptibility gene HLA genes Non- HLA genes Hypersensitivity reflects an imbalance between the effector mechanisms of immune response and the control mechanism that serve to normally limit such response Control mechanism Effector mechanism

7 Human leukocyte antigen In humans the MHC is termed HLA (Human Leukocyte Antigen) Genes located on chromosome 6 It encodes cell surface molecules specialized to present antigenic peptides to the T- cell receptor (TCR) on T cells MHC molecules that present antigen (Ag) are divided into 2 main classes: Class I MHC molecules Class II MHC molecules

8 HLA diseases association Current Genomics, 2007, Vol. 8, No. 7

9 HLA diseases association Many hypotheses have been postulated and generally fall into two categories: (1) Those that blame mistaken identity in which an HLA allele appears to associate with the disease, although the actual culprit belongs to a different locus in the haplotype or associates through linkage disequilibrium (2) Those that implicate immune reactivity to self- antigens due to aberrant T cell repertoire selection, immune cross- reactivity with foreign antigens or immune attack on altered self antigens Discov Med September ; 16(87):

10 Type I: Hypersensitivity reaction

11 Type I : Immediate Hypersensitivity T H 2 cells play a central role in the initiation and propagation of immediate hypersensitivity reactions by stimulating IgE production and promoting inflammation 11

12 Type I : Immediate Hypersensitivity

13 Type I : Immediate Hypersensitivity Immediate (type I) hypersensitivity is a complex disorder resulting from an IgE- mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated mainly by the induction of T H 2 helper T cells that stimulate production of IgE (which promotes mast cell activation), cause accumulation of inflammatory cells (particularly eosinophils), and trigger secretion of mucus. The clinical features result from release of mast cell mediators as well as the eosinophil- rich inflammation

14 Type II: Hypersensitivity reaction

15 Type II : Antibody- Mediated Hypersensitivity Caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix Inflammation (when antibodies deposit) Cellular dysfunction (e.g. myasthenia gravis) Clinically, antibody- mediated cell destruction occur as following: Transfusion reaction Hemolytic disease of newborn (erythroblastosis fetalis) Autoimmune hemolytic anemia Drug reactions myasthenia gravis. (Image by Cumulus, GFDL) 15

16 Type II : Antibody- Mediated Hypersensitivity graves disease (hyperthyroidism symptoms) myasthenia gravis Mechanisms of antibody- mediated injury 16

17 Type II : Antibody- Mediated Hypersensitivity Phagocytosis is largely responsible for depletion of cells coated with antibodies Cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions of some IgG subclasses When IgM or IgG antibodies are deposited on the surfaces of cells, they may activate the complement system by the classical pathway Complement activation generates by- products, mainly C3b and C4b, which are deposited on the surfaces of the cells and recognized by phagocytes that express receptors for these proteins. The net result is phagocytosis of the opsonized cells and their destruction

18 Type II : Antibody- Mediated Hypersensitivity Complement activation on cells also leads to the formation of the membrane attack complex, which disrupts membrane integrity by drilling holes through the lipid bilayer, thereby causing osmotic lysis of the cells This mechanism of depletion is probably effective only with cells that have thin cell walls, such as Neisseria bacteria.

19 Type II : Antibody- Mediated Hypersensitivity 19

20 Type III: Hypersensitivity reaction

21 Type III : Immune complex- mediated hypersensitivity Antigen- antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition Auto- immune disease mechanism Immune complex mediated diseases can be systemic, if immune complexes are formed in the circulation and are deposited in many organs localized to particular organs, such as the kidney (glomerulonephritis) joints (arthritis) IgG/IgM multimers 21

22 Type III : Immune complex- mediated hypersensitivity Pathogenesis of systemic immune complex mediated disease. The three sequential phases in the development of immune complex diseases are shown 22

23 Type IV: Hypersensitivity reaction

24 Type IV : T cell- mediated hypersensitivity The cell- mediated type of hypersensitivity is initiated by antigen- activated (sensitized) T lymphocytes, including CD4 + and CD8 + T cells Many autoimmune diseases are now known to be caused by inflammatory reactions driven by type IV hypersensitivity Reactions of CD4 + T Cells: Delayed- Type Hypersensitivity (DTH) and Immune Inflammation Reactions of CD8 + T Cells: Cell- Mediated Cytotoxicity 24

25 Type IV : T cell- mediated hypersensitivity Mechanisms of T cell mediated (type IV) hypersensitivity reactions 25

26 Type IV : T cell- mediated hypersensitivity Proliferation and differentiation of CD4+ T Cells Responses of differentiated Effector T Cells

27 Type IV : T cell- mediated hypersensitivity Reactions of CD8 + T Cells: Cell- Mediated Cytotoxicity - - CTLs directed against cell surface histocompatibility antigens play an important role in graft rejection The killing of infected cells leads to the elimination of the infection, and is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis) 27

28 Type IV : T cell- mediated hypersensitivity 28

29 Autoimmunity

30 Mechanism of immunological tolerance - The phenomenon of unresponsiveness to an antigen - Self- tolerance = lack of responsiveness to an individual s own antigens, the mechanisms of self- tolerance can be broadly classified into two groups Central Tolerance à negative selection = eliminate self- reactive T cells à receptor editing = eliminate self- reactive B cells Peripheral Tolerance Anergy à irreversible functional inactivation of lymphocyte by costimulatory signals Suppression by regulatory T cells à IL- 10, TGF- β Deletion by activation- induced cell death à if T cells recognize self- antigens, they may express a pro- apoptotic member of the Bcl family, called Bim 30

31 Autoimmunity: Mechanisms Pathogenesis of autoimmunity Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self- tolerance and environmental triggers (tissue injury, inflammation) that promote lymphocyte entry into tissues, activation of self- reactive lymphocytes, and tissue damage 31

32 Autoimmunity: Mechanisms Postulated role of infections in autoimmunity. Infections may promote activation of self- reactive lymphocytes by inducing the expression of costimulators (A), or microbial antigens may mimic self- antigens and activate self- reactive lymphocytes as a cross- reaction (B). 32

33 Conclusion

34 References Y. M. Mosaad, Clinical Role of Human Leukocyte Antigen in Health and Disease. Scandinavian Journal of Immunology, 2015, 82, S.C.L. Gough and M.J. Simmonds. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Current Genomics, 2007, Vol. 8, No. 7 Robbins and Cotran. Pathologic Basis of Disease. 8th edition Saunders Elsevier