Week 16 Flashcards

Question

What are the mechanisms of HLA impact on autoimmune risk/protection?

Answer 1

1. enhances binding to a self antigen: promotes a T cell response to self 2. widespread TCR repertoire shaping 3. HLA locus acts as a transcriptional hub for immune genes (SNPs in this locus than impact expression of immune system genes)

Answer 2

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.

Answer 3

No, it is still a fundamentally stochastic process that will differ significantly between even identical twins - hence, different autoimmune penetrance between twins

Answer 4

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

Answer 5

``` Rheumatoid Arthritis psoriasis lupus myositis scleroderma ankylosing spondylitis ```

Answer 6

Synovial joint lining of articular joints (macrophages and fibroblasts that produce synovial fluid)

Answer 7

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

Answer 8

antibodies against citrullinated proteins (fibrinogen, vimentin) highly specific diagnostic (if you have these, 90% change you will have RA) marker of bone-erosive disease

Answer 9

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

Answer 10

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked. caused my missense mutations in Foxp3.

Answer 11

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

Answer 12

an intracellular receptor for the muramyl dipeptide derived from bacterial peptidoglycan, and its stimulation activates the transcription fac- tor NF􏰝B 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.

Answer 13

represent immediate-type allergic reactions mediated by IgE antibodies, with mast-cell activation the major final effector mechanism

Answer 14

driven by antigen-specific IgG antibodies, the final effector mechanism being complement (type II) or FcR-bearing cellular effectors (type III)

Answer 15

depicted as being driven by cellular effec- tors, including lymphocytes and a variety of myeloid cell types

Answer 16

progression of allergic responses in some individuals from atopic eczema in childhood to allergic rhinitis and eventually to asthma in later life

Answer 17

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

Answer 18

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.

Answer 19

proteases that can cleave desmosomes in the skin. Inhibited by LEKTI.

Answer 20

Frequent person:person contact Natural delivery breastfeeding Farming (dust)

Answer 21

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

Answer 22

Epithelia, microbiota, and immune cells.

Answer 23

skin barrier damage (increased TSLP and IL-33) alterations in the microbiome genetic predisposition epigenetic factors

Answer 24

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.

Answer 25

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.)

Answer 26

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.

Answer 27

Tryptase, chymase, cathespin G, carboxypeptidase These degrade the connective tissue

Answer 28

Histamine and herapin These increase vascular permeability and cause smooth muscle contraction

Answer 29

Th2-polarizing cytokines (IL-4, IL-13, IL-33) Eosinophil-activating cytokines (IL-3, IL-5, GM-CSF) inflammatory cytokines such as TNFa

Answer 30

CCL3, which attracts monocytes, macrophages, and neutrophils

Answer 31

Prostaglandins D2 / E2 Leukotrienes C4, D4, and E4 Platelet activating factor

Answer 32

Eosinophil peroxidase Eosinophil collagenase Matrix metalloproteinase-9

Answer 33

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.

Answer 34

anti-IgE biologic for allergy

Answer 35

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.

Answer 36

FcgRIII binds to immune complexes formed by IgG and allergens, and leads to degranulation, inflammation, etc.

Answer 37

Immediate hypersensitivity is mediated by IgE and mast cells, delayed type hypersensitivity is mediated by Th1 cells.

Answer 38

FceRII, low-affinity IgE receptor present on many cells that may have a role for IgE I:C capture by APCs.

Answer 39

stem-cell factor (ligand for Kit), IL-3, IL-4, and IL-9.

Answer 40

cleaved from membrane phospholipids by phospholipase A2 during cell activation. Its derivative include eicosanoids such as prostaglandins and leukotrienes.

Answer 41

Major prostaglandin produced by mast cells, recruits Th2, eosinophils and basophils. Ibuprofin and aspirin work by inhibiting its synthesis.

Answer 42

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.

Answer 43

specificity for eosinophils: CCL11 (eotaxin 1), CCL24 (eotaxin 2), and CCL26 (eotaxin 3)

Answer 44

CCR3, is quite promiscuous and binds other CC chemokines, including CCL5, CCL7, and CCL13, which also induce eosinophil chemotaxis and activation

Answer 45

released in eosinophil degranulation and causes the degranulation of mast cells and basophils

Answer 46

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.

Answer 47

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

Answer 48

Epinephrine stimulates B-adrenergic receptors, which causes relaxation of airway smooth muscles, and a-adrenergic receptors, which reverses the cardiovascular effects.

Answer 49

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.

Answer 50

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.

Answer 51

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.

Answer 52

rhinovirus infection, which can augment the asthmatic response

Answer 53

T cells are essential for graft rejection. Very few T cells are sufficient for graft rejection.

Answer 54

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.

Answer 55

Occurs within 5-90 days after transplant. Driven by CD8 and CD8s, as well as Mqs. Increased expression of IL-2, IFNg, and TGFB.

Answer 56

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

Answer 57

It seems likely that both contribute somewhat

Answer 58

Haematopoietic stem cell transplant

Answer 59

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.

Answer 60

Occurs after recipient APCs present donor antigen to T cells, thus activating them.

Answer 61

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.

Answer 62

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.