Week 16 Flashcards
How is EAE induced in murine models?
This disease is produced in experimental
animals by injecting them with isolated spinal cord homogenized in complete Freund’s adjuvant.
One of the autoantigens identified in the spinal cord homogenate is myelin basic protein (MBP)
Example of epitope spreading in SLE
B cells with BCRs specific for DNA can also internalize histones and present them to histone-specific T cells via MHC II. These histone-specific T cells can then additionally provide help to histone-specific BCRs, leading to the production of histone-specific antibodies.
autoimmune hemolytic anemia
antibodies against self antigens on red blood cells trigger destruction of the cells, leading to anemia
autoimmune thrombocytopenic purpura
autoantibodies against the GpIIb:IIIa fibrinogen receptor or other platelet-specific surface antigens can cause thrombocytopenia (a depletion of platelets), which can in turn cause hemorrhage.
Flt3l–/– mice
deficient in dendritic cells (DCs)
Batf3–/–
lack cross-presenting DCs
autoimmune surveillance of hypersecreting mutants (ASHM) theory
Postulates that autoimmunity to endocrine and exocrine organs comes from the targeting of hypersecreting parenchymal cells of these organs by the immune system - this typically keeps these organ in proliferative balance, but a shift towards hypersecretion would engender a responding increase in immune reactivity, that could lead to autoimmunity in that organ.
Requirement of autoimmune disease (definition)
- Involve some sort of component of the adaptive immune system (autoantibodies, T cells)
- This leads to an attack on tissue
Causal/associated factors of autoimmune diseases
genetics
physiologic processes
environment
genetic factors influencing autoimmune disease
sex chromosomes
HLA alleles / SNPs
monogenic (rare)
somatic
physiologic factors influencing autoimmune disease
child development/puberty
pregnancy/menopause
stress/depression/cancer
aging/degeneration
Environmental factors influencing autoimmune disease
microorganisms (microbiome)
UV light / food
toxins (carcinogens)
6 mechanisms causing/attributed to autoimmune disease
- loss of tolerance
- alteration of self
- molecular mimicry
- B cell epitope spread
- exposure of a ‘sequestered’ tissue-specific antigen
- overexuberant self-directed turnover
What are general and specific examples of a loss of tolerance in autoimmune disease?
General - loss of Tregs
Specific - escape of TCR clone with high self-reactivity
What are examples of alteration of self that might contribute to autoimmune disease?
neo-antigens from mutations/altered splicing
post-translation modifications
How is B cell reactivity against the placental/trophoblast antigens prevented?
B cells specific for a model trophoblast antigen are strongly suppressed through CD22-Lyn inhibitory signaling, which in turn implicates the sialylated glycans of the antigen as key suppressive determinants.
What might be another role for self-reactive TCRs?
Some T cell subsets have been shown to engage in normality sensing in the skin, wherein they engage in clusters that recognize Skint1 on keratinocytes during homeostasis, which primes them for reactivity if this signaling is disrupted.
Concepts to consider in etiology of autoimmune disease
Is it single-factor (monomeric, one autoAb, etc) or multi-factoral?
Is X a casual driver versus an amplifier (not sufficient alone) versus a response to a pathological event
Is it adaptive cell intrinsic or extrinsic?
Does it promote a specific reaction or a general risk of autoimmunity?
How can genetic association studies assist with the study of the underlying biology of autoimmune disease?
While monogenic associations are rare, they are incredibly helpful for delineating specific pathways.
SNPs can associate either with a generalizable loss of tolerance (many autoimmune disease associations) or one specific autoimmune disease, which can implicate that genetic product as being specific for that single autoimmune disease
What are the two broad impacts of biological sex on autoimmune disease?
system wide amplifiers (sex hormones such as estrogen)
cell-intrinsic impacts (X-linked expression of immune genes)
How might the X chromosome contribute to autoimmune disease?
The X chromosome harbors the highest number of immune-related genes of any chromosome.
X-chromosome inactivation is unique in lymphocytes and pDCs: for example, TLR7 gene escapes X-linked inactivation
GPR174
GPR174 is an X-chromosome-linked G-protein coupled receptor and is thus differentially expressed between males and females.
It interacts with CCL21 in the germinal center - antigen-activated male B cells do not position themselves as efficiently s female B cells in the GC and spend less time in the GC
What are the strongest gene-associations in autoimmune disease?
HLA alleles impose the strongest gene-associations in autoimmunity
Although many HLA alleles are assocaited with heightened risk for autoimmunity, some HLA alleles can even confer protection against autoimmune disease
Which HLA isotypes are the most variable?
HLA-A, HLA-B, and HLA-C of MHCI are all highly polymorphic
For MHCII, HLA-DR Beta chain is also highly polymorphic and associated with many autoimmune diseases
What are the mechanisms of HLA impact on autoimmune risk/protection?
- enhances binding to a self antigen: promotes a T cell response to self
- widespread TCR repertoire shaping
- HLA locus acts as a transcriptional hub for immune genes (SNPs in this locus than impact expression of immune system genes)
Shared Epitope Theory for RA
5 amino acid stretch found in HLA-DRB1 alleles that confer high risk of RA.
This sequence is within the peptide binding pocket and it is hypothesized to promote self-antigen response to citrullinated peptides (post-translationally modified) and promote anti-CCPantibodies, leading to RA.
Do monozygotic twins share TCR repertoires?
No, it is still a fundamentally stochastic process that will differ significantly between even identical twins - hence, different autoimmune penetrance between twins
Mechanism of Rheumatic Fever
Group A streptococcus infection has molecular mimicry against myosin/laminin and the immune system subsequently attacks the cardiac helical proteins with epitope spreading
Associated with HLA-DR7
6 Rheumatic autoimmune disorders
Rheumatoid Arthritis psoriasis lupus myositis scleroderma ankylosing spondylitis
Target of rheumatic arthritis disease
Synovial joint lining of articular joints (macrophages and fibroblasts that produce synovial fluid)
Rheumatoid Factor (RF)
antibodies against Fc portion of IgG
Most often is an IgM
binds immune complexes, generates larger immune complexes
Present in RA and other autoimmune diseases
anti-citrullinated protein antibodies (ACPA)
antibodies against citrullinated proteins (fibrinogen, vimentin)
highly specific diagnostic (if you have these, 90% change you will have RA)
marker of bone-erosive disease
Collagen-induced arthritis (CIA)
an experimental model of RA, in which an inflammatory articular condition is induced in mice by injecting them with an emulsion of complete Freund’s adjuvant and type II collagen
IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked.
caused my missense mutations in Foxp3.
autoimmune lymphoproliferative syndrome (ALPS)
a systemic autoimmune syndrome caused by mutations in the gene encoding Fas
lead to a massive accumulation of lymphocytes, especially T cells, and in mice, to the production of large quantities of pathogenic autoan- tibodies and a disease that resembles SLE
NOD2
an intracellular receptor for the muramyl dipeptide derived from bacterial peptidoglycan, and its stimulation activates the transcription fac- tor NFB and the expression of genes encoding pro-inflammatory cytokines and chemokines
Mutations in NOD2 are highly assocaited with CD, as NOD2 ligation in paneth cells leads to AMP production and the sequestering of commensals to the lumen of the intestine.
Type I hypersensitivity reactions
represent immediate-type allergic reactions mediated by IgE antibodies, with mast-cell activation the major final effector mechanism
Type II or III hypersensitivity reactions
driven by antigen-specific IgG antibodies, the final effector mechanism being complement (type II) or FcR-bearing cellular effectors (type III)
Type IV hypersensitivity reactions
depicted as being driven by cellular effec- tors, including lymphocytes and a variety of myeloid cell types
atopic march
progression of allergic responses in some individuals from atopic eczema in childhood to allergic rhinitis and eventually to asthma in later life
Der p 1
cysteine protease that is present in the feces of the house dust mite. Cleaves occludin present in the tight junctions of airway epithelial cells, leading to a loss of TJ integrity and abnormal access to underlying APCs
Netherton’s syndrome
characterized by high levels of IgE and multiple allergies.
caused by a mutation in serine protease inhibitor LEKTI, expressed in the most differentiated viable layer of the skin. Absence of LEKTI in Netherton’s syndrome results in overly active epidermal kallikreins, proteases that can cleave desmosomes in the skin, leading to keratinocyte shedding and disturbed skin barrier function.
kallikreins
proteases that can cleave desmosomes in the skin. Inhibited by LEKTI.
Environmental factors that correlate with a decrease in allergic disease
Frequent person:person contact
Natural delivery
breastfeeding
Farming (dust)
How does the ‘protective’ lifestyle contribute to decrease in allergic disease?
Immune system is exposed to allergens without the damage of the epithelial barrier, which leads to a lack of IL-33 / GM-CSF / TSLP (alarmins) in the context of sensitization. This leads to tolerogenic DCs that lead to Th1 or Tregs, which induce IgG or IgA as opposed to IgE
Three columns of allergic sensitization
Epithelia, microbiota, and immune cells.
What factors may contribute to the atopic march?
skin barrier damage (increased TSLP and IL-33)
alterations in the microbiome
genetic predisposition
epigenetic factors
Mechanisms of atopic march
There is barrier damage in the context of allergen exposure that leads to the activation of innate cells (eosinophils, basophils, etc.), which then recirculate to other environments in the body (i.e. lung) and re-activate upon re-exposure.
Genes associated with allergic disease
Genes expressed in airway epithelial cells (Chemokines / AMPs/ TJ integrity)
Genes regulating CD4 T cell function and. ILC2 differentiation
(trans factors / cytokines (receptors) / PRRs)
Genes with other functions
(proteinases / signaling proteins / etc.)
How is immediate hypersensitivity set up, using HDM as an example?
House dust mite contains the enzyme Der p 1, which cleaves occludin in the tight junctions of the epithelial barrier. DCs recognize this enzyme and present it in the LN to T cells in the context of Th2 polarizing signals. These Th2 cells induce B cellsto undergo IgE switching, and this IgE is displayed on FcERI on mast cells back at the mucosal barrier.
Enzymes released by mast cells in allergic responses
Tryptase, chymase, cathespin G, carboxypeptidase
These degrade the connective tissue
Toxic mediators released by mast cells in allergic responses
Histamine and herapin
These increase vascular permeability and cause smooth muscle contraction
Cytokines released by activated mast cells in allergic response
Th2-polarizing cytokines (IL-4, IL-13, IL-33)
Eosinophil-activating cytokines (IL-3, IL-5, GM-CSF)
inflammatory cytokines such as TNFa
Chemokine released by activated mast cells in allergic responses
CCL3, which attracts monocytes, macrophages, and neutrophils
Lipid mediators released by activated mast cells in allergic responses
Prostaglandins D2 / E2
Leukotrienes C4, D4, and E4
Platelet activating factor
Enzymes released by eosinophils in allergic responses
Eosinophil peroxidase
Eosinophil collagenase
Matrix metalloproteinase-9
How does epithelial barrier damage lead to allergen sensitization?
Epithelial damage leads to the production of IL-25, IL-33, and TSLP, all of which promote ILC2 and DC activation towards Th2 polarization. Further, the translocation of the microbiota further provides an inflammatory context for these reactions.
omalizumab
anti-IgE biologic for allergy
Three stages of allergen desensitization immunotherapy
Allergen is introduced to the patient either through oral (OIT) or epicutaneous (ECIT - through a patch) in increasing dose escalation under medical observance. This then enters a plateaued maintenance dosing wherein the same dosage is used overa period of months to years. This is then followed by an avoidance phase - the goal is not to completely abrogate the allergic reaction (impossible), but to raise the threshold so that anaphylaxis is less likely following an accidental exposure.
Which receptors on mast cells are responsible for non-IgE mediated allergic responses?
FcgRIII binds to immune complexes formed by IgG and allergens, and leads to degranulation, inflammation, etc.
Delayed type vs immediate type of allergen hypersensitivity
Immediate hypersensitivity is mediated by IgE and mast cells, delayed type hypersensitivity is mediated by Th1 cells.
CD23
FceRII, low-affinity IgE receptor present on many cells that may have a role for IgE I:C capture by APCs.
major factors for mast cell growth and differentiation
stem-cell factor (ligand for Kit), IL-3, IL-4, and IL-9.
Through which adaptor does FcERI signal?
Syk
arachidonic acid
cleaved from membrane phospholipids by phospholipase A2 during cell activation. Its derivative include eicosanoids such as prostaglandins and leukotrienes.
Prostaglandin D2
Major prostaglandin produced by mast cells, recruits Th2, eosinophils and basophils.
Ibuprofin and aspirin work by inhibiting its synthesis.
How do activated eosino[hils regulate Th1 cells?
eosinophils secrete TH2-type cytokines and in vitro can promote the apoptosis of TH1 cells by their expression of IDO and consequent production of kynurenine, which acts on the TH1 cells.
eotaxins
specificity for eosinophils: CCL11 (eotaxin 1), CCL24 (eotaxin 2), and CCL26 (eotaxin 3)
eotaxin receptor on eosinopphils
CCR3, is quite promiscuous and binds other CC chemokines, including CCL5, CCL7, and CCL13, which also induce eosinophil chemotaxis and activation
major basic protein
released in eosinophil degranulation and causes the degranulation of mast cells and basophils
Immediate allergic reaction mediators
IgE-mediated mast-cell activation, leading to the release of histamine, prostaglandins, and others.
This leads to rapid increase in vascular permeability, edema, reddening, and airway narrowing due to smooth muscle contraction.
How does the route off administration of allergen determine the type of IgE-mediated allergic response?
Mast cells assocaited with connective tissue and those associated with mucosa have slightly different reactions to FcERI cross-linking.
Systemic allergen activates connective tissue Mast cells, which leads to systemic release of histamine and other mediators.
mucosa-assocaited mast cells release less histamine, and are chracterized more by smooth muscle contraction and mucus- promotion
How does epinephrine resolve anaphylactic shock?
Epinephrine stimulates B-adrenergic receptors, which causes relaxation of airway smooth muscles, and a-adrenergic receptors, which reverses the cardiovascular effects.
Why is penicillin a common allergen?
Penicillin acts as a hapten, as it is a small molecule with a highly reactive B-lactam ring that can react with amino groups on host proteins to form covalent conjugates.
What happens within chronic exposure of allergen to asthmatic individuals?
This leads to chronic inflammation of the airways, characterized by increased numbers of pathologic lymphocytes and other luekocytes, airway hyperreactivity and tissue remodeling - a thickening of the airways walls due to hyperplasia and hypertrophy of the smooth muscle layer. Also, fibrosis.
Phenotype of mice lacking the transcription factor T-bet
These mice are lacking most Th1 responses, and thus largely polarize towards Th2 responses. They show spontaneous development of asthma-like disease, with airway inflammation and basophils and eosinophils, as well as increased collagen deposition and airway remodeling.
What is one of the main causes of hospitalizations for asthmatics?
rhinovirus infection, which can augment the asthmatic response
Which cells are the most important for transplantation rejection?
T cells are essential for graft rejection. Very few T cells are sufficient for graft rejection.
Hyperacute rejection of solid organs
graft loss within the first 48h of transplant. This is mediated by preformed Abs within the host against transplant endothelial cells. There can also be high-affinity IgG against HLA antigens.
Acute rejection in solid organ transplants
Occurs within 5-90 days after transplant. Driven by CD8 and CD8s, as well as Mqs. Increased expression of IL-2, IFNg, and TGFB.
5 mechanisms of T cell tolerance
Central tolerance in the thymus
Peripheral tolerance: apoptosis post-activation
Anergy induced by TCR stim in absence of co-stim
Suppression by Tregs
Ignorance or physical separation from antigen
Do foreign peptides or foreign MHCs contribute to alloreactivity in transplantation?
It seems likely that both contribute somewhat
HSCT
Haematopoietic stem cell transplant
Direct allorejection
Occurs after donor-derived APCs (passenger leukocytes) migrate to the SLO via the circulation and present their donor-derived peptides to the host immune system. Since the central tolerance of the host may not have presented the same peptides, this can lead to activation of T alloreactive T cell, which in turn migrate to and attack the transplant.
Indirect allorejection
Occurs after recipient APCs present donor antigen to T cells, thus activating them.
Why is direct allorejection often quicker than indirect allorejection?
Direct allorejection is typically via MHC I (since they are cell-derived proteins), and thus activates CD8 T cells.
Indirect involves the uptake of extracellular antigen by APCs and thus is typically MHC II mediated, thus activating primarily CD4s, although these can in turn activate macrophages and other cells that induce cell damage. Cross-presentation can also directly activate CD8s via this route.
Why does hyperacute graft rejection happen so quickly?
This is often due to preexisting alloantibodies in the recipient that are specific for ABO antigens that are present in the endothelium. Complement deposition on the endothelium of the graft results in clotting and destruction of the vasculature, leading to deoxygenation and necrosis of the graft.
