Immunopathology III Flashcards
(32 cards)
(OBJ) Define the mechanisms that lead to immunological tolerance.
Tolerance: the absence of detectable antigen-specific immunity; the absence of pathogenic autoimmunity (or the acceptance of an allograft) ideally achieved without sustained systemic immunosuppression
- Ignorance: antigen inaccessible to immune system
- Negative selection: elimination of potentially autoimmune-reactive T cells before they reach the periphery
- Destruction of T cells in the periphery
- Anergy: antigen encounter -> shutting off of T cells in the periphery
- Tregs -> active suppression of lymphocytes
(OBJ) Describe positive selection and negative selection.
Positive selection: thymocyte must recognize, through the TCR, an MHC/peptide above a certain threshold affinity
Negative selection: too much affinity for MHC/peptides -> deletion
(OBJ) Name possible mechanisms in autoimmunity. (5)
Molecular mimicry Escape of autoreactive clones Release of "sequestered antigen" "Epitope spreading" Polyclonal B cell activation
(OBJ) List genes/loci known or strongly suspected to be associated with autoimmunity in humans. (PTPN22, NOD2, cytokine receptors)
PTPN22
- -encodes PTP (Protein Tyrosine Phosphatase)
- -Associated with RA, T1D, others
- -Gene most frequently implicated in autoimmune disease
- -Postulated: functionally defective, fails to down regulate tyrosine kinase activity in lymphocytes -> hyper-reactive lymphocytes
NOD2
- -Associated with Crohn’s/IBD
- -Encodes a cytoplasmic sensor of microbes in epithelial cells, others
- -Hypothesis – disease allele poor at sensing microbes, allows tissue invasion by microbes, with chronic inflammatory responses against normal commensal bacteria
Cytokine receptors
- -IL-2Rα (aka CD25) and IL-7Rα
- -Associated with MS, others
- -May control the maintenance or development of Tregs
(OBJ) Describe mechanisms by which infection can lead to autoimmunity. (4)
- -Many autoimmune diseases associated with infection
- -Clinical flare-ups often preceded by infectious prodrome
Possible mechanisms:
- Adjuvant effect: up-regulation of co-stimulators on APC may break tolerance for self-antigens
- Molecular mimicry: the microbial antigen looks like human antigen
- —Ex: Rheumatic Heart Disease: Abs against Streptococcal proteins cross-react with myocardial proteins -> myocarditis - Polyclonal B cell activation, augmenting the production of autoantibodies
- —Ex: EBV, HIV - Tissue injury -> release of self-antigens, altered self-antigens -> activation of T cells.
(OBJ) Describe the role of regulatory T cells in controlling autoimmunity. (6)
In vivo studies in mice: certain immunosuppressive cytokines (IL-10, TGF-β1) are important
In vitro studies: cell contact required, cytokines not required
The molecules CTLA-4, FasL, Granzyme, and cell surface TGF-beta1 have all been implicated
(OBJ) Identify diseases mediated by antibodies (5 organ-specific, 1 systemic, 1 microbial Ag-related) and diseases mediated by T cells (2 organ-specific, 3 systemic, 2 microbial Ag-related)
ANTIBODIES:
- -Organ-specific: hemolytic anemia, thrombocytopenia, myasthenia gravis, Graves’ disease, Goodpasture syndrome
- -Systemic: SLE
- -Microbial antigen-related: polyarteritis nodosa
T CELLS:
- -Organ-specific: Type I DM, MS
- -Systemic: rheumatoid arthritis, systemic sclerosis, Sjogren syndrome
- -Microbial antigen-related: IBS (Crohn’s, ulcerative colitis), inflammatory myopathies
(OBJ) Define factors associated with the development of type I diabetes mellitus.
- -Completely T cell mediated destruction of beta cells of pancreatic islet
- -Often preceded by anti-insulin antibodies
- -Antigens: insulin, glutamic acid decarboxylase
- -Strong genetic predisposition
State evidence that negative selection is incomplete. (3)
In a study published 30 years ago by Burns and colleagues…
- -CD4 T cell lines that react with myelin basic protein (a target in multiple sclerosis (MS)) could be isolated from two-thirds of normal human volunteers
- -Proves that there are important tolerance mechanisms operative in the periphery
- -Thymic negative selection shapes repertoire
State evidence for genetic susceptibility in autoimmune diseases. (4)
Genetic susceptibility combines with environmental triggers to result in tissue injury and autoimmune disease
- -Risk is higher in siblings of an index case
- -Risk is much higher in the identical twin of an index case
- -Clear HLA associations: certain haplotypes are associated with certain autoimmune diseases (HLA DR3-A1-B8 -> autoimmune hepatitis)
- —However, HLA haplotype is neither necessary nor sufficient, other genes contribute
- -GWAS: the same genes show up in multiple autoimmune disorders, suggesting mechanisms in common of immune regulation, self-tolerance.
How was the role of Treg cells discovered?
- In the absence of deliberate T cell activation by antigen (whether auto-antigen or cross reactive), pathogenic autoimmunity occurs when selected T cell subsets are depleted
- -3-5 day thymectomy in mice -> poly-autoimmune syndrome, prevented by administration of (CD4+, CD25+) Treg cells
- -There exists a sub-population of regulatory T cells that actively regulate other T cells - Tolerance can be transferred actively from one individual mouse to another —> active, dominant tolerance, not easily explained by simple deletion (i.e. negative selection or peripheral deletion) of a pathogenic subset
List three characteristics of active tolerance
Can be transferred from one individual to another
Can “teach” Ag-specific tolerance to other cells
Can spread tolerance to include additional epitopes
What is CD25? What was it originally cloned as? On what cells is it expressed?
CD25 = low affinity IL-2 receptor (alpha)
–High affinity IL-2 receptor = alpha, beta, and gamma chains
IL-2Ralpha originally cloned as target of monoclonal antibody (MAb) against activated T cells (the “Tac” Mab)
—IL-2Ralpha = “Tac antigen”
Expression of IL-2Ralpha low in resting T cells, rapidly increases upon T cell activation
–>CD25 =/= marker of Treg cells
Overexpressed by T cells in several autoimmune diseases, and allograft rejection (so it can be both good and bad)
Is IL-2 involved in the function of Tregs? Why or why not?
YES. CD25 both marks Tregs and is an IL-2 receptor, implicates IL-2 in the development and or function of Tregs
From where are Tregs derived?
- -Thymus (high avidity to MHC)
- -Can also be generated in the periphery: conventional CD4+CD25- cells can –> regulatory CD4+CD25+ T cells
What is FoxP3?
What does it have to do with Tregs?
How was the link established?
CD4+CD25+ T cells are developmentally regulated by the transcription factor FoxP3
Rare human disease IPEX: --X-linked, single locus genetic autoimmune disease --Neonatal DM --Enteropathy --Endocrinopathy Due to a defect in FoxP3
A defect in what gene causes APECED? What is the normal function of the gene?
AIRE - Negative selection
A defect in what gene causes ALPS? What is the normal function of the gene?
Fas - Peripheral deletion
List four general features of autoimmune diseases.
PROGRESSIVE, with sporadic relapses/remissions
–Suggests intrinsic amplification mechanisms associated with antigen-specific lymphocytes
EPITOPE SPREADING: tissue damage -> release of self antigens -> new exposed epitopes -> increased immune response
CLINICAL AND PATHOLOGIC MANIFESTATIONS determined by nature of immune response
- -Th1 = MO-rich inflammation, Ab production -> complement
- -Th17 = neutrophils
OVERLAP: between different autoimmune diseases clinically, pathologically, and serologically
Classify the following autoimmune diseases as involving type II or type III hypersensitivity:
- -Autoimmune hemolytic anemia, neutropenias, lymphopenias, thrombocytopenia
- -Bullous skin diseases (Pemphigus, Pemphigoid)
- -Goodpasture disease
- -Graves disease
- -Myasthenia gravis
- -Polymyositis-dermatomyositis
- -Rheumatoid arthritis
- -Sjogren syndrome
- -Systemic lupus erythematosus (SLE)
- -Systemic sclerosis (scleroderma)
- -Autoimmune hemolytic anemia, neutropenias, lymphopenias, thrombocytopenia: Type II
- -Bullous skin diseases (Pemphigus, Pemphigoid): Type II
- -Goodpasture disease: Type II
- -Graves disease: Type II
- -Myasthenia gravis: Type II
- -Polymyositis-dermatomyositis: Type III
- -Rheumatoid arthritis: Type III
- -Sjogren syndrome: Type III
- -Systemic lupus erythematosus (SLE): Type III
- -Systemic sclerosis (scleroderma): Type III
(OBJ) Describe the etiology (a summary) associated with systemic lupus erythematosus.
ETIOLOGY: SLE is a complex disorder of multifactorial origin resulting from interactions among genetic, immunological, and environmental factors that act in concert to cause activation of helper T cells and B cells and result in the production of several species of pathogenic autoantibodies.
(OBJ) List the manifestations associated with systemic lupus erythematosus.
MANIFESTATIONS: hematologic, arthritis, skin, fever, fatigue, weight loss, renal, CNS, pleurisy, others
(OBJ) Describe the pathogenesis associated with systemic lupus erythematosus.
PATHOGENESIS: persistent high-level anti-nuclear IgG antibody production
(OBJ) Describe genetic factors associated with systemic lupus erythematosus.
GENETIC FACTORS: very complex, from MHC and non-MHC genes
- -Increased risk in family members and monozygotic twins
- -HLA associated
- -Some have defect in complement, may favor tissue deposition rather than removal
