immunopathology III - lecture notes - julia Flashcards
what is tolerance?
- strict definition: absence of detectable antigen-specific immunity
- clinical definition: absence of pathogenic autoimmunity
what are the possible mechamisms for tolerance? (5)
- ignorance: antigen is inaccessible to the adaptive immune system
- negative selection: autoimmune t cells are destroyed before they reach the periphery
- t cells are destroyed in the periphery before, as, or after they encounter antigen
- anergy: t cell encounter antigen in such a way as to subsequently leave them ineffective
- T-regs suppress other lymphocytes
how does positive selection occur?
- thymocyte must recognize, through the TCR, MHC/peptide above a certain threshold of affinity
- if it doesn’t, it will die through neglect
how does negative selection occur?
- in thymus
- t cell has too high of an affinity for a peptide
- causes signal for cell death in that thymocyte
what are the possible mechanisms in autoimmunity? (5)
- molecular mimicry
- escape of autoreactive clones
- release of “sequestered antigen”
- “epitope spreading”
- polyclonal B-cell activation
what is epitope spreading?
- a possible mechanisms of autoimmunity
- initially the epitopes that the system is responding to are low, but they spread as the disease progresses
- part of molecular mimicry mechanisms
- according to wiki: “autoreactive T cells to be activated de novo by self epitopes released secondary to pathogen-specific T cell-mediated bystander damage. T cell responses to progressively less dominant epitopes are activated as a consequence of the release of other antigens secondary to the destruction of the pathogen with a homologous immunodominant sequence. Thus, inflammatory responses induced by specific pathogens that trigger pro-inflammatory Th1 responses have the ability to persist in genetically susceptible hosts. This may lead to organ-specific autoimmune disease.”
what is the evidence that negative selection is incomplete?
- multiple sclerosis
- the MBP protein is in myelin
- can cluture T cells from patients without MS that respond to MBP
- indicates ability to isolate self-reactive t cell clones from normal individuals
- indicates existance of peripheral tolerance mechanism (otherwise these people would have MS)
- therefore, thymic negative selection on its own is not sufficient to shape the T cell repertoire
what factors are required for autoimmunity to occur?
- must have genetic susceptibility
- must have some kind of environmental effect such as infection or tissue damage or exposure to certain chemicals
- the genetic problem will lead to malfunction of one of the steps in the diagram (it’s just of the normal steps of immune cell development after activation) when the immune system tries to respond to the enviromental factor
what can influence genetic susceptibiilty for autoimmunity? what is the evidence that it’s genetic?
- evidence:
- increased risk in siblings of index case
- very large increased risk in identical twins of index case
- HLA seems to be most important in determining autoimmunity
- eg certain haplotypes have been associated with certain autoimmune diseases
- note that genetic susceptibility is neither necessary nor sufficient for autoimmune disease
what is the role of PTPN-22 in autoimmune disorders?
- gene assosiated allele can be defective
- codes for a phosphatase involved in removing phosphate from tyrosines in the signaling pathway involved in mediating signaling from lymphocyte receptors including t cell receptors
- if defective, proteins will be phosphorylated for longer => overactive lymphocytes
- gene has been associated with retioic acid, type I diabetes, and other autoimmune diseases
what is the role of NOD-2?
- associated with crohn’s disease
- encodes for a cytoplasmic sensor of microbes on epithelial and other cells
- thought that the diseased allele is poor at sensing microbes => tissue invasion by these microbes => chronic inflammatory responses => promotes inflammatory response in whole intestine => destruction of normal commensal bacteria
what is the role of IL-7 receptor alpha in autoimmune disease?
- associated with MS and other diseases
- may control maintenance or development of tregs
what is the role of infection in the development of autoimmune disease?
- clinical flare-ups often preceded by infectious prodrome
- by adjuvant effect or molecular mimicry (see additional cards)
what are the possible mechanisms by which an infection can trigger autoimmune disease? (4)
- adjuvant effect - upregulation of co-stimulators on APC => breaking of tolerance for self-antigens
- molecular mimicry - microbial antigen looks like human antigen
- polycolonal B cell activation => augmentation of production of autoantibodies (EBV, HIV)
- tissue injury releases or alters self-antigens => activation of T cells
describe how autoimmunity can be triggered by induction of constimulators on APCs versus molecular mimicry
- when induction of costimulators on APCs occurs:
- microbe infects/encounters cells that will express that antigen
- that cell has some self antigen on MHC
- that cell will now activate APC
- you now have, from a T cell’s point of view, a legitimate combination that drives its proliferation
- => reaction with sefl tissue
- in molecular mimicry:
- microbe that’s taken up by APC that presents antigen and the right costimulator
- t cells now recognize an antigen that’s very close to an autoantigen
- therefore, the t cell will attack self cells
what is thought to be the major mechanism that drives anergy?
encoutering of self peptide signal 1 in the absence of signal 2 (B7)
what is the evidence that there is a subpopulation of regulatory t cells that actively regulate other t cells?
- in the absence of deliberate t cell activation by antigen, pathogenic autoimmunity occurs when selected t cell subsets are depleated
- experiments in mice - something important happens between days 3-5 after birth:
- remove thymus at 3-5 days of age
- this removes the ability to develop new t cells, but they’ve already developed some
- these mice will develop autoimmunity to some tissues
- if you remove the thymus earlier, these mice are just immuodeficient
- if you remove the thymus later, they’re fine
- all of this indicates that there’s something critical happening during days 3-5 in mice to prevent autoimmunity
what are some characteristics of active tolerance? (3)
- antigen-specific tolerance can be transfered from one individual to another (only shown in animals)
- can “teach” antigen-specific tolerance to other cells
- can spread tolerance to include additional epitopes
how were CD4+/CD25+ cells discovered?
- had been previously established that depletion of certain subpopulation of t cells => organ specific autoimmune disease of GVHD-like wasting disease
- so some group went looking for them - just looked at ton of different possibilities
- were looking at CD5(high) and CD45RB(low)
- cd4+/CD25+ appears to be a subset of these
really don’t think we need to know this…
what is CD25? (ie what kind of protein, what’s its function, what’s its structure, what cell types is it used as a marker for?)
- alpha chain serves as a low-affinity IL-2 receptor
- alpha, beta, and gamma (common) chains serve as high-affinity IL-2 receptors
- it was originally discorved as a target of MAb that activates T cells
- IL-2R(alpha) is therefore known as Tac antigen
- expression of IL-2R(alpha) is low in resting t cells - rapidly increases upon T cell activation
- used as marker for Treg cells and for “typical” t cells that have been activated
- it’s overexpressed by t cells in several autoimmune diseases and in allograft rejection
how/where are CD4+/CD25+ T cells made?
- in the thymus, via the high avidity model (explained later)
- in the periphery, perhaps from a pool of CD25- (regular) T cells
- conventional t cells being converted to T reg cells in this case
- separage lineage, developmentally regulated by FoxP3
describe the high avidity models of Treg selection
- Treg cells arise from relatively high-avidity interactions with self-peptide MHC compexes just below the thershold for negative selection (green area)
- ensures T reg cells will constitute only a small fraction of mature T cell pool and will have a greater sensitvity to self-peptide-MHC than potentially pathogenic autoreactive T cells
- so in this graph - too high avidity is negative selection
- too low avidity is death by neglect
what is FoxP3? how is it involved in autoimmune disorders?
- discovered when researching neonatal diabetes:
- IPEX = x-linked disorder
- caused by defect in this gene
- causes problems in Treg function - get destruction of pancreatic cells
- example of one of the few single-locus autoimmune diseases
what is required for Tregs to suppress other cells?
- in vivo, cytokines are required (IL-10, TGF-beta1)
- in vitro, cell contact is required, but cytokines aren’t
what factors to Treg cells use to suppress other cells?
- CTLA-4 suppresses cells
- TGF-beta may also suppress cells
- FasL
- Granzyme
- possible homeostatic mechanisms
how do progressive autoimmne disorders develop/present?
- will have sporadic relapses/remissions
- implies intrinsic amplification mechanisms associated with antigen-specific lymphocytes
- in that situation, flareups would be due to expansion of subsets
how can epitope spreading create autoimmune disease?
- tissue damage causes release of self antigens and exposes epitopes previously hidden
- new epitopes trigger new autoreactive t cell reactions
- as a result, the immune response spreads to epitopes not previously recognized
what determines the clinical and pathogic manifestations of an autoimmune disease?
- the nature of the underlying immune response
- Th1 = macrophage rich inflammation, production of antibodies that can activate complement
- Th17 = neutrophil rich inflammation - Th17 drives chemokine expression
what are the categories of autoimmune diseases mediated by antibodies and immune complexes? (3)
- organ-specific
- systemic
- those caused by autimmunity or by reactions to microbial antigens
what clinical symptoms would you see in SLE patients?
- acute malar rash (butterfly eruption - picture)
- fever
- malaise
- joint pain
- myalgias
- fatigue
- temporary loss of cognitive abilities
what would you expect to see in the heart of SLE patients upon autopsy?
libman-sacks vegetations - sterile
what would you expect to see histologically in the heart of SLE patients?
- vegetations (the darker areas)
- sterile fibrin platelet aggregates in tricuspid valve in this picutre
- no inflammation in the vegetations
- but could have myocarditis too (inflammation in the myocardium - not in this picture)
what would you expect to see histologically in the skin of SLE patients? (H&E and immunoflorescence)
- liquefactive degeneration of the basal layer of the epidermis
- edema at the dermoepidermal junction
- immuno for IgG will reveal deposits of Ig along dermoepidermal junction
what would you expect to see in the retina of an SLE patient?
- arterial occlusion with retinal vasculitis
- in this picture, in the top right you can see one vessel that looks pinched (it disappears and then reappears) - this is the site of occlusion
what would you expect to see histologically in patients with RA?
- marked synovial hypertrophy with formation of villi at low magnification
- subsynovial tissue containing a dense lymphoid aggregate in high magnification image
what immunological mediators have been found to be involved in RA? which one has been targed for treatment?
- mediators include:
- IL-1, 6, 17, 23
- TNF
- PGE2
- GM-CSF
- NO
- TGF-beta
- MMPs
- RANKL
- TNF antagonists have had some success in treating RA - indicates that TNF is really important in development of disease
review: what are the actions of TNF?
- secreted by monocytes
- activates endotehlial cells to increase surface adhesion molecules => increased adherence of T cells and monocytes from in vessels
- activates synovial fibroblasts
=> secretion of IL-8 => increased migration through endotehlium into synovial tissue
also => secretion of matrix MMPs, PG E2, IL-6 => attack on cartilage - activates monocytes to secrete IL-1
=> activates synovial fibroblasts
also => activation of T cells
what would you expect to see in the x-ray of the hands of patients with RA?
- diffuse osteopenia
- marked loss of the joint spaces of carpal, metacarpal, phalangeal and interphalangeal joints
- periarticluar bony erosions
- ulnar drift of the fingers
what is bursitis? what does it look like?
- inflammation of one or more small sacs of synovial fluid in RA
what would a subcutaneous rheumatoid nodule look like histologically?
- area of necrosis surrounded by palisade of macrophages and scattered chronic inflammatory cells
what would you expect to see in the lung xray of patients with RA?
- pulmonary fibrosis/nodules
