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56 Cards in this Set
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AIRE=
Mechanism= Human Disease |
Auto Immune Regulatory Gene
Failure of Central Tolerance causes APS-Autoimmune Polyendocrine Syndrome |
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C4
Mechanism: Disease |
Defective clearance of Immune Complexes. Failutre of B-cell tolerance
causes SLE |
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CTLA-4
Mechanism? Human Disease? |
Failure of Anergey in CD4+ T Cells
Associated with several AutoI disease |
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Fas/FasL
Mech? Dx? |
Defective deletion of Anergic self-rxn B-cells; reduced deletion of mature CD4+ T cells
Causes: ALPS AutoI Lympho-Prolif. Syndrome |
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FoxP3
Mech? Dx? |
Deficiency of regulatory T cells
causes IPEX: Imm. dysreg., Polyendocrinopathy, Enteropathy, X-linked synd.. |
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IL-2; IL-2Ralpha/beta
Mech: Dx? |
Defective development, survival, or fxn of regulatory T-cells
Causes--none known (In mice: IBD, anti-eryth & antiDNA) |
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SHP-1
Mech Dx |
Failure of Negative Reg of B-cells
Causes: none known (In mice: multiple autoAbs |
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CTLA-4 =
Is a? |
Cytotoxic Lymphocyte Ag-4.
CD-28 family Receptor |
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Anergy
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Normal action, prevents T-cell from doing shit when there is no co-stimulation--T-cell will arrest-maybe apoptose. Loss of anergy would be rogue T-cell
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IIMs
3 Types |
Idiopathic Inflammatory Myopathies:
Dermatomyositis (DM) Polymyositis (PM) Inclusion Body Myositis (IBM) |
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Subacute onset. Sym. patterns. Skin d and Prox. muscle weaknes. Heliotrope rash eyelids and elsewhere.
Erythema of knuckles. Myalgia |
DM, Dermatomyositis
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Insidioius Onset/slow progresn. Prx. and dist. muscle weakness and atrophy. No response to steroids. Weakness/atrophy can by aysmmetric
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IBM, Inclusion Body Myositis
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Adult with subacute, Prx. and sym. myopathies.
Neither IBM nor DM? |
Polymyositis.
Freq. overlaps with SLE and SSc( SjorgensSyn) and other AutoIm dx. Can be drug induced. |
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Which IIMyopathy is mediated by Th2 cells/humoral? Complement
Which by Th1 (macs)/cellmediated)? |
DM=Th2/humoral
PM & IBM = Th1/cell-mediated |
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IBM Features?
Eosinophilic Inclusion Bodies Contents (3 items) |
Vacs w/ debris (membranous)
1. B-amyloid precur. PR (BAPP) 2. Ubiquitin 3. APOE--apolipoprotein -- think Prion too--- |
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IBM Treatment--most common
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Methotrexate & azathioprine
Cyclosporin or cyclophasphamide Tacrolimus & mycophenolate (if response to others is poor, prevent humoral proliferation |
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Type III RA
Ag-AB complexes release BLANK from fixed complement |
anaphylatoxisn C3a and C5a
--Vasoactive amines from Neutrophils too --Cause Vasculitis |
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RA with infiltrating T-lymphos, B-lymphos, MNcytes and Macs, Neutrs.
Th1 type response (CD4+) |
Type IV Hypersensitivity
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Type IV Hypersensitivity mediators
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TNF-a and IL-1 CENTRAL to damage. IFN-gamma impt to act MAcs and induce endo cells to induce prd of above + IL-6
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FS--Felty Syndrome
Triad-= |
1. neutropenia, 2, splenomegaly, 3, lymphadenopathy
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RA Treatment
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Analgesics, NSAIDs, DMADs-(dx modifying antirRh. dgs),
Recombinant & Soluble Cytokine Receptors (antagonist for normal receptors) Steroids. do not improve long-term prognosis |
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NSAID Cyclooxygenase Inhibition of COX-2 blocks?
COX-1? |
Prostaglandins syn--reduces pain and inflm.--COX-2
Blocks Thromboxane syn. (side-effects)--COX-1 |
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Selective COX-2
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effective for pain, may Inc. risk of Myocardial Infarcts
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DMADs used
axn? |
1. Methotrexate
--inhib of dihydrofolate reductz--synthesis of THYMIDINE--inhibits prolif of rapidly dividing Immune Cells (normal epi cells too-side effect) |
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Steroids inhibit
IL-2 effect |
Translation of cytokines: 1-6,8 and TNF-alpha--= decrease Inflm
--dec. B-cell expansion/Ab syb If IL-2 dec, less T-cell Prolif |
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Steroids induce?
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induce trans of Anti-Inflam PR
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What Dx is characterised by PolyClonal B-cell Activation and Hyper-gamma-globulinemia
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SLE: Primary Findings
Inflammation Vasculitis & Vasculopathy -Imm Complex Deposition |
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SLE is what Type Hypersensitivty
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Type III--
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Type III Hypersensitivity Char.?
Complexes? Complement? Which Inflam Cells |
Ag-Ab complexes
C3a & C5a Anaphylatoxins Neuts and basophils--release vasoactive amines |
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Impaired clearance of Immune Complex by Phagocytes is pathogenic for What?
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SLE
-Has Anti-DNA Abs in assc w/ Glomerulonephritis |
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SLE susceptability depends on what MHC class II genes?
2 specific genes ? |
HLA Class II & Class III genes
HLA-DR2 and HLA-DR3 |
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SLE susceptability depends on what MHC class III genes?
3 specific genes ? |
HLA Class III for Complement
-C1 -C2 -C4A Null alleles (high risk!!) |
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NON MHC suceptability Genes?
3 Cytokines 3 for Clearance Ab-Ag complexes |
TNF-Alpha!!, IL-6, T-Cell Receptor
CR1, FcyRIIA (IgG Fc rec), FcyRIIIA (IgG Fc rec) |
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Specific Viral DNA found in 100 % SLE patients.?
Bacterial Component cause? |
Ep. Barr
Endotoxin in maybe |
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Most obvious environmental factor for SLE inflammation adn apoptosis
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UV light exposure
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Auto-Ags are processed into peptides and presented in What?
Presented mainly to What cell? |
Class II MHC molecules TO
T Helper Cells (Th2)--help B-cells produce Abs=polyclonal B cell activation. |
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APC MHC II B7 + T Cell CD28 =
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stimulatory=
cytokine release |
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MHC II B7 + T Cell CTLA4 =
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anergy/inhibition
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When B-Cell is APC, and the T-Cell is already activated (early from some infx by a DC-APC) so it expresses CD40
B-APC CD40 + T Cell CD40L= |
Stimulation-Cytokines
IL-10 !!! Class switching IgM to IgG (IgG can penetrate deeper, ex, glomerulus of kidney) |
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IL-10
What Type of Th cytokine? High serum IL-10 correlates with High what? |
potent stim of B-cell Prolif/Diff
-is a Th2 cytokine -with high anti-DNA Abs |
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4 reasons why pathogenic B cells not found in healthy (significant levels)
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1. Central Tolerance: self-rxn-B-cells deleted
2. B-cells remain, but a re anergic 3. Receptor editing of light chain 4. Regulatory T-Cells (Treg cells) suppress the activation of Th cells |
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Treg Cells:
subset of what? serume level in SLE? Diagnostic Abs for lab check? 2. |
subset of CD4 cells
Level is reduced in SLE pts CD4 and CD25 (specific to Treg) |
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What can be loaded in MHC II molecules
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Peptides ONly--NO DNA (no self DNA)
But B-cell can pick up Pr assc. w/ DNA |
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What receptor does Activated T cell present, that Naive doesn't.
What does Naive have reqd for Act. |
CD40 Receptor (Ligand can be B-cell)
Naive will have CD28 (for B7 on APC) to be activated by APC |
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How T-cell can recognize/activate Self-Reactive B-cell.
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Collateral Damage from Infxn, releases Infx-Ags used by APC to activate T-cells. Simult. damage releases Self-DNA/Pr that B-cell is reactive to, and the activated T-cell stims the B-cell (displaying normal Infxn-Ag, but happens to be auto-reactive for self DNA too). Thus, activated T-cell Activates auto-B cell (which just reacted to normal infx) for class switching=Auto Immune IgG Response to DNA. Thus, T-cell INDIRECTLY responds to non-Peptide (DNA) extracellular blebs
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Anti-Nuclear Antibodies SPECIFIC for SLE
2 3 other non-specifics, but present in AutoImn |
Anti-ds-DNA
Anti-Sm (anti Smith) -Anti-RNP, Anti-Ro, Anti-La (Ro & La assc w/ Sjorgens too) |
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Anti-dsDNA most closely asscociate with ??? Lupus
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Kidney Lupus
Lupus Nephritis |
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Describe mechanism for Type II and Type II Hypersensitivities for Glomerulonephritis
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Type III--anti-dsDNA-Ab-Ag formed in circulation (Abs bind to circulating nucleosomes) and then deposit
Type II--Formed in situ anti-dsDNA Abs cross react with peptides in the kidney then activate complement |
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SLE has Th ? dominated response
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Th2, where IL-10 is dominent over IL-12
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Receptor and Ligand for SLE apoptosis.
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Fas/FasL
inc. Apoptosis = more self reactive Ags |
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Mediators for Defective Clearance in SLE
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C2, C4, C1q
--the early complement proteins Fc Rec abnormalities in Macs |
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Summary Qs
Key Cellular Interaction for SLE? |
CD4+ T-helper Cells and Bcells
Though T cells specific for auto_Ag are found |
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Name 2 Preformed Mediators of Acute Allergic Rhinitis?
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Histamine
tryptase |
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Name 2 de Novo Mediators of Acute Allergic Rhinitis?
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Leukotrienes
PGD2 ---big role in development in Nasal Congestion |
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Which cells predominate in nasal secretions
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Basophils
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For Hygiene Hypothesis, an INC or DEC in number/activity of T-Regulatory Cells causes alleregies
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Decrease number/activity of Treg Cells. These are inc. after infxn. With fewer infxn. double wammy!
(other wammy is part of Hypoth is shift from Th1 --> Th2 type biase from lack of exposure) |
