Immunology Flashcards
2 mécanismes de défense du système immunitaire
Innate
Adaptive
Caractéristiques de l’immunité innée
« One size fits all » (no specificity)
Fast
No memory
Evolutionarily « old »
Components of Innate Immunity
Physical barriers : kin, corneal epithelium, orbital septum, etc.
Chemical : cytokines, lysozymes in tears, complement, fever
Non-specific effector cells
- Phagocytes = macrophages, dendritic cells
- Granulocytes (PMNs) = neutrophils, basophils, eosinophils, mast cells, NK cells
Innate Immunity Triggers
Bacterial-derived molecules
- Cell wall : lipopolysaccharide (LPS), lipotheichoic acid, HSP
- Exotoxins : collagenases
Non-specific molecules (recruitment) : complement, histamine, prostaglandins, ROS, cytokines…
Caractéristiques des prostaglandines
Vascular permeability
Capillary permeability → CME
Prostaglandin analogs involved in uveoscleral outflow
- First line agent for POAG
- Theoretical risk of increasing CME in uveitis patients = try to avoid in uveitis
Types of cytokines
Cytokines : broad term describing small proteins involved in cell signaling
Involved in BOTH innate and adaptive immune system
Types :
- Chemokine : involved in movement of cells (chemoattractant)
- Interleukins (IL) : promote development and differentiation of T + B cells
- Interferons (IFN) : produced in response to viral infected cells → upregulates NK cells and macrophages. Linked to « flu like symptoms » (= souvent les ES des Tx interferons)
- Tumor Necrosis Factor (TNF) : screwed by macrophages and CD4+ TH1. Prepares endothelium by vasodilatation and increasing permeability, adhesion
Caractéristiques de l’immunité adaptative
Highly specific
Slow (days)
Has memory
Evolutionarily « new » (only present in vertebrates)
Components of Adaptative Immunity
Humoral
- B cell mediated
- Mature cells secrete soluble Ig into extracellular fluid
Cellular
- T cell mediated
- Involves synthesis of cytokines + initiation of adaptive immune response
Caractéristiques de l’immunité humorale
Antibodies secreted by activated B cells
Target pathogens for opsonization
Neutralize receptors on bacterial or viral surfaces
Inactive circulating toxins
2 types de T cells dans l’immunité cellulaire
CD4 (helper T cells)
- Work with B cells to increase antibodies (Ab) production
- Always ask for this in HIV + patients
CD4 > 200 = systemically asx :)
CD4 < 200 = systemically symptomatic :(
CD4 < 50 = ocular manifestations
CD8 (cytotoxic T cells)
- Kills target or host cells infected by other pathogens
Types of CD4 cells
TH1
- Interacts with mononuclear phagocytes and helps destroy intracellular pathogens
- Secretes : IFNy, TNF-a, GM-CSF, IL-2
TH2
- Interact with B cells and helps them to divide, differentiate and make Ab
- Secretes : IL-4, IL-5, IL-10, IL-13, TGF-B
TH17
- Enhance neutrophil response to extracellular pathogens
- Secretes : IL-17, IL-21, IL-22, IL-26
T-Reg
- Maintains lymphocyte homeostasis (turn off active immune cells)
- Secretes : TGF-B, IL-10, IL-35
3 signals required for T-Cell activation
- T-Cell receptor binding with MHC (major histocompatibility complex)
- CD28 binding with B7 (CD80/86) on APC
- Cytokine activation e.g. IL-2, IL-12
Caractéristiques du Major Histocompatibility Complex (MHC)
MHC in humans is called HLA (human leukocyte antigen)
Prevents inbreeding (more HLA diversity → improved survival)
- Inbreeding = cosanguinité
- Lots of genetic diversity in form of subgroups (>25 A’s, 50 B’s, 10 C’s, 100 DR’s)
Located on chromosome 6, short arm
MHC molecules present glycoproteins to activate adaptative immune response
Caractéristiques du MHC Class I
MHC I region = HLA A, B, C
Present on all cells (except mature RBC)
Purpose is to present endogenous Ag (often virus) to CD8+
CD*+ kills cells that display foreign Ag in MHC class I
Increase in transcription by IFN-alph, beta or gamma
Caractéristiques du MHC Class II
MHC II region = HLA DR, DQ, DW
Present only on APC (macrophages, dendritic cells and some B cells)
Present exogenous Ag (phagocytosed) to CD4+ cells
CD4 activate other effectors of immune system
Increase transcription of IFN-gamma
MHC heritability
HLA heritability is transferred as one set of 6 major HLA subtypes (A, B, C, DR, DQ and DW)
1/4 siblings have identical HLA (important for organ transplant)
HLA association : DRB1
DRB1 = Tubulointerstitial Nephritis and Uveitis Syndrome (TINU)
HLA association : A29
A29 = Birdshot Chorioretinopathy
- > 90% positivity
- Env. 8% de la population caucasienne
HLA association : B27
B27 = AAU, AS, IDB, PsA, Reactive Arthritis
- Env. 8% de la population caucasienne
HLA association : B51
B51 = Behcets Diasease
HLA association : DR4
DR4 = SO, VKH
HLA association avec l’AJI
A2
DR5
DR8
DR11
HLA association avec intermediate uveititis
B8
B51
DR2
DR15
HLA association avec la sarcoïdose
B8
B13
HLA association avec la SEP
B7
DR2
HLA association avec Retinal Vasculitis
B44
Panuvéite versus Endophtalmie
Panuveitis : descriptive term and does NOT imply etiology
Endophtalmitis : panvuveitis secondary to infection
Vrai ou Faux. Les stéroïdes inhibent les phospholipases, enzymes en amont de la cascade inflammatoire.
Vrai.
S’il n’y a pas de réponse au Tx, requestionner le Dx pr r/o cause infectieuse ou néoplasique
Solutions : Acetates versus Phosphates
Acetates/Alchohols = Lipophilic
+ : augmentation [ ] intraoculaire
- : shaking required
Phosphates = Hydrophilic
+ : no shaking required
- : diminution [ ] intraoculaire
2 principaux ES oculaires des corticostéroïdes
Cataractes
IOP
Plus la puissance est élevée, plus le risque est grand
Nommez différents corticostéroïdes topiques en ordre de puissance
Puissance faible à élevée :
Loteprednol etabonate 0,2% (Alrex)
Fluorometholone 0,1% (FML) = Loteprednol etabonate 0,5% (Lotemax)
Prednisolone Phosphate 1% (not commonly seen)
Prednisolone Acetate 1% (PF) = Dexamethasone Phosphate 0,1% (Maxidex)
Difluprednate 0,05% (Durezol)
General approch for non-infectious uveitis Tx
Anterior (w/o CME)
- Topical steroids (typically Prednisolone 1%) +/- cycloplegia if PS
- Systemic IMT if severe anterior uveitis not maintained on ≤ 2 drops of PF
Anterior (+ CME)
- Topical steroids (durizol aka difluprednate 0,05%)
- Local steroids versus systemic IMT if bilateral or recalcitrant
Intermediate/Posterior/Panuveitis
- Local steroid versus systemic IMT (drops alone won’t cut it)
Algorithme sélection Tx IMT
- Rule out systemic + local infx
- Prednisolone 60 mg (steroid sparing IMT if > 10 mg/d or < 3 mois)
- Antimetabolites (MTX, MMF, CsA, AZA)
- Anti-TNF : Adalimumab → Infliximab
3rd line :
- CsA
- Daclizumab (anti-IL2)
- Toxilizumab (anti-IL6)
- IFN
4th line : Bring out the Big Guns
- Alkylating agents (CP, chlorambucil)
- Rituximab
Special situations
- Local Tx (PSTK, IVK, Ozurdex, Retisert)
- IV steroids
MMF : mycophenolate
CsA : cyclosporine-A
What is the mediator of the anti-inflammatory effects of MTX?
Extracellular release of adenosine (/!\ PAS inhibition of folate metabolism)
Mécanisme d’action du MTX + posologie
Folic acid analogue + inhibitor of dihydrofolate reductase → inhibits DNA replication
Anti-inflammatory effect = realize of extracellular adenosine
Posologie :
- PO ou s/c
- 20 mg (minimal ocular dose)
- q1sem
- AF 1mg PO die
Therapeutic in environ 3 mois
Mécanisme d’action du MTX + posologie Mycophenolate Mofetil (CellCept)
Inhibitor of IMPDH enzyme involved in purine synthesis/DNA replication
Posologie :
- PO
- 1000 mg BID (minimal ocular dose)
Therapeutic in environ 3-4 weeks
(work faster, lower s/e profile)
Nom commercial du mycophenolate mofetil
CellCept
Mécanisme d’action du MTX + posologie de l’azathioprine
Converted to 6-MP → inhibit purine synthesis/DNA replication
Posologie :
- PO
- 1-2 mg/kg (ocular dose)
Therapeutic in environ 3 months
Nom commercial de l’azathioprine
Imuran
Monitoring des anti-metabolites
FSC
Créatinine
Bilan hépatique
Test de grossesse
Azathioprine : doser l’activité de l’enzyme TPMT avant début Tx (déficience possible et toxicité 2nd)
Médicaments inhibiteurs de la calcineurine
Cyclosporine
Tracolimus
Mécanismes d’action et ES des calcineurin inhibitors
Inhibit NF-AT (nuclear factor of activated T lymphocytes) reducing T cell transduction and IL-2 production (needed for T-cell activation)
Both CsA and Tracrolimus requires trough levels
Both equally effective, tacrolimus better tolerated
ES :
- CsA : systemic HTN, nephrotoxicity (avoid Rx in elderly)
- Tacromlimus = nephrotoxicity
Nom générique de l’Humira
Adalimumab
Efficacité de l’Adalimumab
Even though the initial success rates are high…
With a conservative measure about ONE THIRD will eventually need another strategy
L’Adalimumab (Humira) is the first and only FDA approved biologic drug for the Tx of post/pan uveitis
Classe biologique de l’Adalimumab (aka MA)
Anti-TNF
Contre-indications des anti-TNF
Untreated latent TB (risk of reactivation)
Demyelinating disease (peut exacerber la maladie, penser à faire un screening chez les jeunes F)
Moderate to severe CHF
Recent LIVE vaccination (MMR, yellow fever, BCG, etc.)
Chronic or active hepatitis
Active severe infection
Active malignancy
Mécanisme d’action et indications du Tocilizumab
Anti-IL6
Indications
- JIA associated uveitis
- Anterior uveitis
- Intermediate uveitis
- Post/Pan uveitis
Lequel des Rx est associé à un « mental health concerns » comme ES
IFN
Mécanisme d’action et indications du Rituximab
Humanized monoclonal anti-CD20 antibody (B-cells)
Goal : remove B-cell clones responsible for the production of pathogenic autoantibodies
Longer term effect > 6-9 months
Indications :
- Behçet’s disease
- OCP
- Ophtalmie GPA
- Orbital inflammation
- Scleritis dans rheumatoid arthritis (RA)
- VKH
- Birdshot chorioretinopathy (BCR)
- Autoimmune retinopathy (AIR)
- Peripheral ulcerative keratitis (PUK)
- JIA
