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Flashcards in immunopathology III - lecture notes - julia Deck (73)
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1
Q

what is tolerance?

A
  • strict definition: absence of detectable antigen-specific immunity
  • clinical definition: absence of pathogenic autoimmunity
2
Q

what are the possible mechamisms for tolerance? (5)

A
  • 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
3
Q

how does positive selection occur?

A
  • thymocyte must recognize, through the TCR, MHC/peptide above a certain threshold of affinity
  • if it doesn’t, it will die through neglect
4
Q

how does negative selection occur?

A
  • in thymus
  • t cell has too high of an affinity for a peptide
  • causes signal for cell death in that thymocyte
5
Q

what are the possible mechanisms in autoimmunity? (5)

A
  1. molecular mimicry
  2. escape of autoreactive clones
  3. release of “sequestered antigen”
  4. “epitope spreading”
  5. polyclonal B-cell activation
6
Q

what is epitope spreading?

A
  • 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.”
7
Q

what is the evidence that negative selection is incomplete?

A
  • 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
8
Q

what factors are required for autoimmunity to occur?

A
  • 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
9
Q

what can influence genetic susceptibiilty for autoimmunity? what is the evidence that it’s genetic?

A
  • 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
10
Q

what is the role of PTPN-22 in autoimmune disorders?

A
  • 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
11
Q

what is the role of NOD-2?

A
  • 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
12
Q

what is the role of IL-7 receptor alpha in autoimmune disease?

A
  • associated with MS and other diseases
  • may control maintenance or development of tregs
13
Q

what is the role of infection in the development of autoimmune disease?

A
  • clinical flare-ups often preceded by infectious prodrome
  • by adjuvant effect or molecular mimicry (see additional cards)
14
Q

what are the possible mechanisms by which an infection can trigger autoimmune disease? (4)

A
  • 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
15
Q

describe how autoimmunity can be triggered by induction of constimulators on APCs versus molecular mimicry

A
  • 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
16
Q

what is thought to be the major mechanism that drives anergy?

A

encoutering of self peptide signal 1 in the absence of signal 2 (B7)

17
Q

what is the evidence that there is a subpopulation of regulatory t cells that actively regulate other t cells?

A
  • 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
18
Q

what are some characteristics of active tolerance? (3)

A
  • 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
19
Q

how were CD4+/CD25+ cells discovered?

A
  • 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…

20
Q

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?)

A
  • 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
21
Q

how/where are CD4+/CD25+ T cells made?

A
  • 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
22
Q

describe the high avidity models of Treg selection

A
  • 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
23
Q

what is FoxP3? how is it involved in autoimmune disorders?

A
  • 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
24
Q

what is required for Tregs to suppress other cells?

A
  • in vivo, cytokines are required (IL-10, TGF-beta1)
  • in vitro, cell contact is required, but cytokines aren’t
25
Q

what factors to Treg cells use to suppress other cells?

A
  • CTLA-4 suppresses cells
  • TGF-beta may also suppress cells
  • FasL
  • Granzyme
  • possible homeostatic mechanisms
26
Q

how do progressive autoimmne disorders develop/present?

A
  • 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
27
Q

how can epitope spreading create autoimmune disease?

A
  • 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
28
Q

what determines the clinical and pathogic manifestations of an autoimmune disease?

A
  • 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
29
Q

what are the categories of autoimmune diseases mediated by antibodies and immune complexes? (3)

A
  • organ-specific
  • systemic
  • those caused by autimmunity or by reactions to microbial antigens
30
Q

what are some examples of organ-specific autoimmune disease? (5)

A
  1. autoimmune hemolytic anemia
  2. autoimmune thrombocytopenia
  3. myasthemia gravis
  4. graves disease
  5. goodpasture syndrome (kidney, lung)
31
Q

what is an example of a systemic autoimmune disease?

A

systemic lupus erythematosus (SLE)

32
Q

what is an example of a disease caused by autoimmunity or reactions to microbial antigens?

A

polyarteritis nodosa

33
Q

what are the two classes of diseases mediated by T cells?

A
  1. organ-specific autoimmune diseases
  2. systemic autoimmune diseases
34
Q

what are some examples of organ-specific autoimmune diseases mediated by T cells? (2)

A
  • type I diabetes mellitus
  • multiple sclerosis
35
Q

what are some examples of systemic autoimmune diseases mediated by T cells? (3)

A
  1. rheumatoid arthritis
  2. systemic sclerosis
  3. siogren syndrome
36
Q

what are the most common types of reactions (or combination of types of reactions) that result in autoimmunity? (3)

A
  1. predominantly type II or III
  2. predominantly type IV (mediated by T lymphocytes)
  3. mixed T cell and B cell
37
Q

what is the evidence that genetic factors predispose people to SLE? (5)

A
  1. 20% increased risk for first degree relatives
  2. monozygotic twins have a 20% risk, as opposed to a 2% risk for dizygotic twins
  3. specific HLA-DQ alleles associated with anti-dsDNA, anti-Sm, and anti-P have been identified
  4. about 6% of Sle patients have a deficiency in C2, C4, or C1q - this lack of C’ may impair the removal of Ab/Ag complexes
  5. an animal model has been made that has about 20 distinct susceptibility loci
38
Q

how are failures of tolerance involved in the development of SLE? (2)

A
  • failure of self-tolerance => defective elimination of self-reactive B cells
  • failure of tolerance to eliminate CD4+ cells specific for nucleosomal antigens
39
Q

how may nuclear DNA/RNA be involved in the occurance of SLE? (2 ways)

A
  • the DNA/RNA in immune complexes may engage TLRs on DNA/RNA-specific B lymphocytes
  • (remember that some TLRs recognize bacterial DNA or RNA => drives adjuvant response)
  • PBL that are normally produced in response to viral DNA/RNA are overreactive in SLE patietns
40
Q

how may BAFF be involved in SLE?

A
  • cytokine
  • may augment B cell survival
41
Q

what enviornmental factors can contribute to SLE? (3)

A
  1. exposure to UV light
    - possible induces cellular apoptosis and alters DNA so that it becomes immunogenic
    - therefore would have enhanced TLR recognition and it would exacerbate the disease
  2. sex hormones
    - during reproductive eyars, frequency of SLE in women is 5-10 time greater than before or after reproductive years
  3. drugs
    - hydralazine, procainamide, D-penicillamie
    - can induce SLE-like response
42
Q

describe how SLE can be triggered and develop (cellular level pathology)?

A
  • patient has suceptibility genes driving a failure in self tolerance
  • some external trigger, such as UV damage, drives the apoptosis of cells
  • this results in increased burden of nuclear antigens
  • increased nuclear antigens + possibly changed antigens + susceptibility => development of autoantibodies
  • antigen/antibody complexes develop
  • get high levels of anti-DNA substances
43
Q

what clinical symptoms would you see in SLE patients?

A
  • acute malar rash (butterfly eruption - picture)
  • fever
  • malaise
  • joint pain
  • myalgias
  • fatigue
  • temporary loss of cognitive abilities
44
Q

what would you expect to see in the heart of SLE patients upon autopsy?

A

libman-sacks vegetations - sterile

45
Q

what would you expect to see histologically in the heart of SLE patients?

A
  • 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)
46
Q

what would you expect to see histologically in the skin of SLE patients? (H&E and immunoflorescence)

A
  • 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
47
Q

what would you expect to see in the retina of an SLE patient?

A
  • 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
48
Q

what population is most likely to have rheumatoid arthritis? (gender and age) how many people does it affect?

A
  • women 3-5x more likely
  • most common in people from 40-70 years
  • affects about 1% of world’s population
49
Q

what organs does RA affect?

A
  • mainly the joint but also:
  • skin
  • blood vessels
  • heart
  • lungs
  • muscles
50
Q

what does RA cause in the joints that results in pain? (what’s the pathogenesis of the disease?)

A
  • non-suppruative proliferative/inflammatory synovitis
  • progresses to destruction of articular cartilage and ankylosis of joints
51
Q

what are the three factors that are required for the acquisition of RA?

A
  1. genetics
  2. environment
  3. immunological abnormalities
52
Q

what are the clinical symptoms of RA? (7)

A
  • fatigue
  • weight loss
  • myalgias
  • excessive sweating
  • low-grade fevers
  • morning stiffness
  • lymphadenopathy
53
Q

what are the morphological changes in the joints seen in RA patients? (7 - summary card (each one will have it’s own card too…))

A
  • infiltration of synovial stroma by dense perivascular inflammatory infiltrate (consists of t helper cells, B cells, plasma cells, DC, macrophages)
  • increased vascularity due to vasodilation and angiogensis
  • aggregation of fibrin covering portions of the synovium and floating in the joint space
  • accumulation of neutrophils in the synovial fluid
  • osteoclastic activity in underlying bone - synovium will penetrate bone => erosions, cysts, osteoporosis
  • pannus formation
  • once cartilage is destroyed, fibrous ankylosis, pannus bridge across apposing bones
54
Q

what would you expect to see in the synovial stroma in patients with RA?

A
  • infilatration by dense perivascular inflammatory infiltrate
  • t helper cells
  • b cells
  • plasma cells
  • DCs
  • macrophages
55
Q

what changes would you expect to see in the vasculature in the joints of patients with RA?

A

increased vascularity due to vasodilation and angiogensis

56
Q

what would you expect to see in the synovial fluid of patients with RA?

A
  • accumulation of neutrophils
  • possible aggregated fibrin floating in joint space
57
Q

what would you expect to see in the bone of patients with RA?

A
  • osteoclastic activity in the underlying bone
  • synovium will penetrate bone => erosions, cysts, osteroperosis
58
Q

what is a pannus?

A
  • forms in RA patients
  • mass of synovium and stroma with inflammatory cells, granulation tissue, synovial fibroblasts
  • grows over the articular cartilage and causes its erosion
  • once the cartilage is destroyed, it will be the bridge across apposing bones
59
Q

what would you expect to see histologically in patients with RA?

A
  • marked synovial hypertrophy with formation of villi at low magnification
  • subsynovial tissue containing a dense lymphoid aggregate in high magnification image
60
Q

what are the known genetic factors that contribute to RA?

A
  • contributions from MHC and multiple non-MHC genes
  • regarding MCH - the specific HLA-DRB1 allele is associated
  • PTPN22 allele
61
Q

what environemental factors may contribute to the initiation of RA? (2 categories)

A
  1. viruses/bacteria
    - EBV
    - parvoviruses
    - mycobacteria
    - borrelia
    - mycoplasma
  2. citrullinated proteins
    - argnine modified to citrulline
    - seen in the lungs of smokers
62
Q

what are the immunologic factors involved in the development of RA? (what cell types are most involved? what is the inticing antigen?

A
  • inflammatory synovitis => autoimmune reaction - t cells have pivitol role
  • inticing antigen not clear - possibly type II collagen or glycosaminoglycans
  • mostly T cells involved
  • CD4+ cells appear in joint early
  • Th17 recruit neutrophils
  • Th1 involved in activation of macrophages
63
Q

what is the role of rheumatoid factor in RA?

A
  • 80% of patients have it
  • it’s the autoantibody most commonly found to be associated wiht RA
  • they’re autoantibodies against the Fc portion of IgG
  • typically IgM themselves (but can be other types)
  • these aren’t causative, but are a marker of the disease
64
Q

how has anti-CCP been found to be involved in RA?

A
  • antibody against citrullinated peptides
  • present in most people with RA but really rare in others
  • produced at sites of inflammation
  • if you increase anti-CPP and you have a T-cell response to CPP => chronicity
65
Q

what immunological mediators have been found to be involved in RA? which one has been targed for treatment?

A
  • 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
66
Q

review: what are the actions of TNF?

A
  • 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
67
Q

what would you expect to see in the x-ray of the hands of patients with RA?

A
  • diffuse osteopenia
  • marked loss of the joint spaces of carpal, metacarpal, phalangeal and interphalangeal joints
  • periarticluar bony erosions
  • ulnar drift of the fingers
68
Q

what are the extra-articular manifestations of RA?

  • eye =
  • pleura =
  • lung =
  • pericardium =
  • spleen =
  • gut =
  • bone marrow =
  • skin =
  • nervous system =
  • muscle =
  • kidney =
  • lymph nodes =
A
  • eye = scleritis keratoconjunctivitis
  • pleura = effusions
  • lung = fibrosis nodules, effusions
  • pericardium = effusions
  • spleen = spleenomegaly
  • gut = amyloidosis
  • bone marrow = anemia, thrombocytosis
  • skin = thinning, ulceration
  • nervous system = peripheral neuropathy, mononeritis multiplex
  • muscle = wasting
  • kidney = amyloidosis
  • lymph nodes = reactive lymphadenopathies
69
Q

what is bursitis? what does it look like?

A
  • inflammation of one or more small sacs of synovial fluid in RA
70
Q

what would a subcutaneous rheumatoid nodule look like histologically?

A
  • area of necrosis surrounded by palisade of macrophages and scattered chronic inflammatory cells
71
Q

what would you expect to see in the lung xray of patients with RA?

A
  • pulmonary fibrosis/nodules
72
Q

what percentage of the population is affected by type I diabetes mellitus? what causes it?

A
  • 1-3%
  • due to autoimmune destruction of the beta cells of pancreatic islets
73
Q

what immune cells and antigens are involved in type I DM?

A
  • T cell mediated (both CD4+ and CD8+)
  • often preceded by anti-insulin antibodies
  • antigens include insulin and GAD