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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
Q

Psoriasis Plaques

A

Itchy

Hypervascularized - The plaques bleed if you scratch them

26
Q

The cost of treating Psoriasis with one year of Ustekinumab induction and maintenance

A

$53,909

Make damn sure the patient is HLA-C*06:02 positive before you prescribe them that price tag

27
Q

When do the autoantibodies characteristic of each Class II MHC-associated autoimmune disease develop?

A

Years to decades before there is any evidence of tissue inflammation

28
Q

Natural History of a Rheumatic Disease

A

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
Q

Transient Weak ANA positivity

A

Could be part of the polyclonal B cell activation of EBV infection. ANA positivity is common even without autoimmune diseases.

30
Q

Who has autoantibodies that react with nuclear antigens at a dilution of 1:160?

A

SLE Patients
Some other autoimmune diseases
~10% of the apparently normal population

31
Q

Hep 2

A

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
Q

Patterns you’ll see on Autoantibody staining

A 
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
Q

During the clinical silent phase of autoimmunity, how does the autoimmune response expand and strengthen?

A

T Cell activation
Clonal expansion
Differentiation into injurious memory/effector status
Induction of B cells to produce autoantibodies

34
Q

Result of B Cells being induced to produce autoantibody by CD4 T Cells

A

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
Q

If you see IgG autoantibodies

A

You know there is a T cell presiding over that B cell and telling it to try harder

36
Q

Natural antibodies

A

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
Q

Anti dsDNA Ab

A

Highly specific for SLE (>50 - 75%)

38
Q

Anti ssDNA Ab

A

Very nonspecific. Everyone has this.

39
Q

Anti-Histone Ab

A

Found in bout 30 - 40% of SLE patients

Found in >90% of drug (hydralazine)-induced Lupus

40
Q

Extractable Nuclear Antigens (ENA)

A

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
Q

Anti-U1 RNP

A

Found in 30% of SLE patients, as well as some other systemic autoimmune diseases
U1 RNP is a component of the spliceosome

42
Q

MCTD - Mixed Connective Tissue Disease

A

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
Q

Anti-Smith Ab (anti-Sm)

A 
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
Q

Anti-Ro (Anti-SS-A) - Ro60, Ro52
Anti-La (Anti-SS-B) - La

When are these present?

A

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
Q

What are La and Ro proteins involved in doing?

A

Regulation of eukaryotic translation and transcription factor binding

46
Q

Pro-inflammatory signals that enhance the response to immune complexes

A

Anti DNA/nucleoprotein complex binding to TLR9

Anti ribonucleoprotein-RNA complexes binding to TLR7

47
Q

Where are TLR9 and TLR7 located?

A

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
Q

Smoking

A

High Relative Risk for most autoimmune conditions

Rheumatology (16 decks)

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