Autoimmune Diseases Flashcards
Autoimmune response
Immune response that causes autoimmune disease and it produces state of autoimmunity
- mechanisms of antigen recognition and effector function in autoimmunity are the same as those used in responding to pathogens and environmental antigens
Autoimmune diseases
Focus on particular organ or cell type, others are systemic
- females more commonly affected
Autoimmune disease components
Presence of antibodies (autoantibodies) and T cells (autoimmune T cells) specific for antigens expressed by the targeted tissue (autoantigens)
Damaging responses are due to ____
Immune effector mechanisms
Mechanisms that contribute to immunological self tolerance
- negative selection in bone marrow and thymus
- expression of tissue-specific proteins in the thymus
- no lymphocyte access to some tissues
- suppression of autoimmune responses by Tregs
- induction of anergy in autoreactive B and T cells (absence of costimulatory signal)
Types of autoimmunity
2: antibody against cell surface or matrix antigens
3: immune-complex disease
4: T cell mediated disease
Autoimmune hemolytic anemia
- type 2
- autoantigen: Rh blood group antigens, I antigen
- consequence: destruction of RBC by complement and phagocytes, anemia
Graves’ disease
- type 2
- autoantigen: thyroid-stimulating hormone receptor
- consequences: hyperthyroidism
Myasthenia gravis
- type 2
- autoantigen: acetylcholine receptor
- consequences: progressive weakness
Type 2 diabetes (insulin resistant)
- type 2
- autoantigen: insulin receptor (antagonist)
- consequences: hyperglycemia, ketoacidosis
Systemic lupus erythematosus
- type 3
- autoantigen: DNA, histones, ribosomes, snRNP, scRNP
- consequence: glomerulonephritis, vasculitis, arthritis
Type 1 diabetes (insulin dependent)
- type 4
- autoantigen: pancreatic beta cell antigen
- consequence: beta cell destruction
Rheumatoid arthritis
- type 4
- autoantigen: unknown synovial joint antigen
- consequence: joint inflammation and destruction
Multiple sclerosis
- type 4
- autoantigen: myelin basic protein, proteolipid protein
- consequence: brain degeneration, paralysis
3 mechanisms that destroy RBCs in autoimmune hemolytic anemia
Erythrocytes bind anti-erythrocyte autoantibodies
- FcR+ cells in spleen = phagocytosis and RBC destruction
- complement activation and CR1+ cells in spleen = phagocytosis and RBC destruction
- complement activation and intravascular hemolysis = lysis and RBC destruction
Autoantibodies against cell-surface receptors can either ____ or ____ receptor’s function
stimulate (agonist); inhibit (antagonist)
Agonist: Graves’ disease and hypoglycemia
Antagonist: Myasthenia gravis and Insulin-resistant diabetes
Myasthenia gravis mechanism
Signaling from nerve to muscle across the neruomuscular junction is impaired by autoantibodies
Systemic lupus erythematosus
- autoantigen: nucleosomes
- pathogenic antibody: IgG
- type 3 = large amount of immune complexes formed that deposit in capillaries of tissues (enter thru fenestrations and become trapped in basement membrane)
How does lupus involve all aspects of the immune response?
T cells: pathogenic, help for antibody
B cells: present antigen to T cells
Antibody: pathogenic
SLE mechanism of autoantigen accumulation
Possible defects in the clearance of apoptotic cells
- macrophages from SLE patients have a reduced capactiy to engulf apoptotic cells in vitro
Type 1 diabetes mechanism
T cell responses and antibodies are made against insulin and other specialized proteins of pancreatic beta cell islets
What causes rheumatoid arthritis?
Effector CD4 T cells and antibody
- antibodies bind to all B cells in the body, Fc portion binds to NK cells = lysis of all B cells
- ADCC: lysis of B cells by NK cells and therapeutic anti-CD20 antibody rituximab
Therapy of rheumatoid arthritis
Anti-TNF alpha
Breaking T cell tolerance is a feature of all autoimmune diseases
- incomplete deletion of self-reactive T cells in the thymus, autoimmune polyendocirnopathy-candidiasis-ectodermal dystrophy
- insufficient control of T cell co stimulation (CTLA-4 deficiency)
- lack of Tregs, deficiency in foxP3 = immune dysregulation, polyendocrynopathy, enteropathy and X linked syndrome
____ is the dominant genetic factor affecting susceptibility to autoimmune disease
HLA
- B27, A29, DQ6 found in >95% of patients and have a relative risk of >150
Autoimmunity is initiated by
Disease associated HLA allotypes presenting antigens to autoimmune T cells - greater number of HLA class 2 is expected because they present antigens to CD4 T cells
Autoimmune response is started by _______
Autoreactive T cells being stimulated by specific self peptide MHC
Autoimmunity is _____ and tolerance is the ______
Exception; rule!
- when tolerance is broken it involves just one autoreactive T cell clones that initiate autoimmunity
Animal models of autoimmune disease demsonstrated that autoreactive T cell clones can _______
Transfer disease
Infections as environmental factors that can trigger autoimmune disease
- streptococcal cell wall stimulates antibody response
- some antibodies cross-react with heart tissue, causing rheumatic fever
Autoimmune T cells can be activated in a pathogen-specific or non-specific manner by infection
Same MHC molecule presents both a pathogen peptide and a self peptide that mimics it –> naive T cell is activated by the pathogen peptide presented by particular MHC –> effector Th1 cell responds to self peptide mimic and activates the macrophage = inflammation
______ of the T cell population can contribute to autoimmunity
Senescence
Genetic factors that predispose to autoimmune disease
Different MHC class 1 and 2 allotypes correlated with different disease suceptibilites and may present autoantigens to tolerance-breaking T cells - HLA accounts for half of genetic predisposition, other factors include proteins in thymic selection and control of T cell activation
Environmental factors that predispose to autoimmune disease
- damage integrity of tissues and stimulate adaptive immunity
- trauma, chemical, irradiation, certain food
Difficulties in identification of the infectious triggers of autoimmune diseases
- infections are successfully resolved and rarely recorded
- symptoms of autoimmune disease usually begin long after the event that triggered the response
