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Rheumatology > 6 - Mechanisms of Autoimmunity > Flashcards

6 - Mechanisms of Autoimmunity Flashcards

1
Q

Autoimmune Disease

A

Results from a T-cell driven immune system response within the adaptive immune system directed to certain self-peptides causing clinically distinctive patterns of tissue injury and inflammation

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2
Q

The central event in the adaptive immune system

A

Recognition of a particular peptide selectively bound to an MHC molecule

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3
Q

Central abnormality of autoimmunity

A

A T cell clone specifically recognizes and persistently responds to a self-peptide anomalously presented by a particular allomorphic MHC molecule

p-MHC

The T cell in repertoire is not “tolerant” of self p-MHC
It transitions from a quiescent T cell to one responding strongly to a self-peptide

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4
Q

What determines the features of different autoimmune diseases?

A

The nature and tissue location of the protein containing the autoantigen peptide driving the response.

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5
Q

Systemic Lupus Erythematosus - Associated MHC Allele

A

HLA-DRB115:01 (DR2), DRB103

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6
Q

Sjogren’s Syndrome - Associated MHC Allele

A

HLA-DRB1*03

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7
Q

Rheumatoid Arthritis

A

HLA-DRB104, DRB101, etc (Shared Epitope)

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8
Q

Multiple Sclerosis

A

HLA-DRB1*15:01 (DR2)

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9
Q

Type I Diabetes Mellitus

A

HLA-DRB104, DRB103 (‘DQ*8’)

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10
Q

What is the shared epitope, really?

A

It’s a binding pocket that’s common to all the allelic molecules involved in the various syndromes which “share” that epitope.

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11
Q

MHC Class II associated diseases

A

Mediated by CD4 T Cells which help B cells make autoantibodies

SLE
Sjogren's Syndrome
Rheumatoid Arthritis
Multiple Sclerosis
Type I Diabetes Mellitus
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12
Q

MHC Class I associated diseases

A

Mediated by CD8 T Cells, with no involvement from autoantibodies

Ankylosing Spondylitis
Psoriatic arthritis
Psoriasis

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13
Q

Ankylosing Spondylitis - Associated MHC Allele

A

HLA-B*27

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14
Q

Psoriatic Arthritis - Associated MHC Allele

A

HLA-C06:02, HLA-B27, HLA-B*08

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15
Q

Psoriasis - Associated MHC Allele

A

HLA-C*06:02

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16
Q

Where is the MHC causing all systemic rheumatic disease located?

A

Chromosome 6

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17
Q

How does Diabetes I work?

A

HLA-DQ8 presents a peptide to the thymus that is actually self because the HLA didn’t dimerize, so it fits things that it wouldn’t normally fit.

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18
Q

How do you treat Psoriasis?

A

Inhibit IL-17 and/or IL-23

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19
Q

Ustekinumab

A

Inhibits IL-12 and IL-23
Treats Psoriasis

HALF of the caucasian patients will respond dramatically and completely to this treatment
White patients positive for HLA-C*06:02 tend to respond well.
Chinese patients positive for that same allele yielded similar results, but that allele is much less common in Chinese patients, so most Psoriasis in Chinese individuals is not treatable with this drug.

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20
Q

Briakinumab

A

Inhibits IL12 and IL-23

Treats Psoriasis

21
Q

IL-17 Pathway

A

Begins in Macrophages and Dendritic Cells
They make IL-23
IL-23 acts on a receptor (on Th17 cells and γδT Cells) partially shared by IL-12
This triggers Th17 cells and γδT Cells to release many cytokines, one of which is IL-17

22
Q

Low amounts of IL-17

A

Critical for epithelial integrity

23
Q

Greater amounts of IL-17

A

Potent mediator in cellular immunity:
Increases chemokine production
Recruits monocytes and PMNs to the site of inflammation
Acts similarly to IFN-γ

24
Q

Psoriasis

A 
Affects ~3% of the population, hella common
Mediated by CD8 T cells
Infiltrate basal layers of skin
Release cytokines
Thwart normal keratinocyte maturation
25
Psoriasis Plaques
Itchy | Hypervascularized - The plaques bleed if you scratch them
26
The cost of treating Psoriasis with one year of Ustekinumab induction and maintenance
$53,909 | Make damn sure the patient is HLA-C*06:02 positive before you prescribe them that price tag
27
When do the autoantibodies characteristic of each Class II MHC-associated autoimmune disease develop?
Years to decades before there is any evidence of tissue inflammation
28
Natural History of a Rheumatic Disease
Genetic Predisposition (p-MHC-TCR) How and which peptides are presented Self T Cell repertoire selection Environmental Trigger - Bypassing checkpoint Loss of tolerance of one or a few clones to a self-antigen (Low positive for antibodies) Inappropriate self-recognition by antibodies Environmental Trigger - Bypassing checkpoint Inflammation and target organ damage (High positive for antibodies)
29
Transient Weak ANA positivity
Could be part of the polyclonal B cell activation of EBV infection. ANA positivity is common even without autoimmune diseases.
30
Who has autoantibodies that react with nuclear antigens at a dilution of 1:160?
SLE Patients Some other autoimmune diseases ~10% of the apparently normal population
31
Hep 2
From a human laryngeal carcinoma line Used as a substrate to test for ANA Put patient's serum on a cover slip with Hep2 and stain for IgG
32
Patterns you'll see on Autoantibody staining
``` Homogeneous Speckled-Centromere Fine Speckled Rim Centromere + Mitochondria Homogeneous-Nucleolar Centromere Mitotic spindle Anti-mitochondria-ANA-neg Anti-Golgi ``` Each of these reflects different dominant nuclear targets of different autoimmune responses.
33
During the clinical silent phase of autoimmunity, how does the autoimmune response expand and strengthen?
T Cell activation Clonal expansion Differentiation into injurious memory/effector status Induction of B cells to produce autoantibodies
34
Result of B Cells being induced to produce autoantibody by CD4 T Cells
Increasing quantities of autoantibody (titres) Isotype switch to IgG Maturation to higher affinity antibodies through somatic mutation Spreading of immune response to additional epitopes on the initial autoantigen and to additional molecules
35
If you see IgG autoantibodies
You know there is a T cell presiding over that B cell and telling it to try harder
36
Natural antibodies
Low Titre No somatic mutation IgM isotype (don't switch isotypes) Often seen transiently with B cell stimulation, as with infection of the B cell by EBV during infectious mono
37
Anti dsDNA Ab
Highly specific for SLE (>50 - 75%)
38
Anti ssDNA Ab
Very nonspecific. Everyone has this.
39
Anti-Histone Ab
Found in bout 30 - 40% of SLE patients | Found in >90% of drug (hydralazine)-induced Lupus
40
Extractable Nuclear Antigens (ENA)
Smallecules that diffuse out of a slightly damaged nuclear envelope They aren't nucleoproteins, but they are other constituents of the nucleus Potential targets for different types of autoantibody
41
Anti-U1 RNP
Found in 30% of SLE patients, as well as some other systemic autoimmune diseases U1 RNP is a component of the spliceosome
42
MCTD - Mixed Connective Tissue Disease
Distinctive syndrome with VERY elevated titers of anti U1-RNP Features of non-renal lupus, polymyositis and limited scleroderma Long term, these cases may settle into a more classic pattern of SLE, myositis or limited scleroderma
43
Anti-Smith Ab (anti-Sm)
``` Mainly IgG subclass Suggests T-Cell dependence ``` T cells recognizing Sm peptides have highly restricted TCR usage This indicates only a small number of autoreactive clones This indicates antigen-driven response The most sensitive and specific for SLE in a person with a positive ANA
44
Anti-Ro (Anti-SS-A) - Ro60, Ro52 Anti-La (Anti-SS-B) - La When are these present?
Primary Sjogren's Syndrome (≥95%) Subacute cutaneous lupus erythematosus (~100%) SLE (10 - 60%) Neonatal Lupus (100%) ANA-negative Lupus Erythematosus SLE-like disease in homozygous C2 or C4 complement deficiency
45
What are La and Ro proteins involved in doing?
Regulation of eukaryotic translation and transcription factor binding
46
Pro-inflammatory signals that enhance the response to immune complexes
Anti DNA/nucleoprotein complex binding to TLR9 | Anti ribonucleoprotein-RNA complexes binding to TLR7
47
Where are TLR9 and TLR7 located?
In the endosome Dependent on lysosomal acidification and partial digestion of complexes ingested via FcR or CR This location provides a rationale for the use of hydroxychloroquine to prevent processing of complexes
48
Smoking
High Relative Risk for most autoimmune conditions

Rheumatology (16 decks)

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