6 - Mechanisms of Autoimmunity Flashcards Preview

Rheumatology > 6 - Mechanisms of Autoimmunity > Flashcards

Flashcards in 6 - Mechanisms of Autoimmunity Deck (48):
1

Autoimmune Disease

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

2

The central event in the adaptive immune system

Recognition of a particular peptide selectively bound to an MHC molecule

3

Central abnormality of autoimmunity

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

4

What determines the features of different autoimmune diseases?

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

5

Systemic Lupus Erythematosus - Associated MHC Allele

HLA-DRB1*15:01 (DR2), DRB1*03

6

Sjogren's Syndrome - Associated MHC Allele

HLA-DRB1*03

7

Rheumatoid Arthritis

HLA-DRB1*04, DRB1*01, etc (Shared Epitope)

8

Multiple Sclerosis

HLA-DRB1*15:01 (DR2)

9

Type I Diabetes Mellitus

HLA-DRB1*04, DRB1*03 ('DQ*8')

10

What is the shared epitope, really?

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

11

MHC Class II associated diseases

Mediated by CD4 T Cells which help B cells make autoantibodies

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

12

MHC Class I associated diseases

Mediated by CD8 T Cells, with no involvement from autoantibodies

Ankylosing Spondylitis
Psoriatic arthritis
Psoriasis

13

Ankylosing Spondylitis - Associated MHC Allele

HLA-B*27

14

Psoriatic Arthritis - Associated MHC Allele

HLA-C*06:02, HLA-B*27, HLA-B*08

15

Psoriasis - Associated MHC Allele

HLA-C*06:02

16

Where is the MHC causing all systemic rheumatic disease located?

Chromosome 6

17

How does Diabetes I work?

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.

18

How do you treat Psoriasis?

Inhibit IL-17 and/or IL-23

19

Ustekinumab

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.

20

Briakinumab

Inhibits IL12 and IL-23
Treats Psoriasis

21

IL-17 Pathway

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

Low amounts of IL-17

Critical for epithelial integrity

23

Greater amounts of IL-17

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

24

Psoriasis

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