6 - Mechanisms of Autoimmunity Flashcards
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
The central event in the adaptive immune system
Recognition of a particular peptide selectively bound to an MHC molecule
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
What determines the features of different autoimmune diseases?
The nature and tissue location of the protein containing the autoantigen peptide driving the response.
Systemic Lupus Erythematosus - Associated MHC Allele
HLA-DRB115:01 (DR2), DRB103
Sjogren’s Syndrome - Associated MHC Allele
HLA-DRB1*03
Rheumatoid Arthritis
HLA-DRB104, DRB101, etc (Shared Epitope)
Multiple Sclerosis
HLA-DRB1*15:01 (DR2)
Type I Diabetes Mellitus
HLA-DRB104, DRB103 (‘DQ*8’)
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.
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
MHC Class I associated diseases
Mediated by CD8 T Cells, with no involvement from autoantibodies
Ankylosing Spondylitis
Psoriatic arthritis
Psoriasis
Ankylosing Spondylitis - Associated MHC Allele
HLA-B*27
Psoriatic Arthritis - Associated MHC Allele
HLA-C06:02, HLA-B27, HLA-B*08
Psoriasis - Associated MHC Allele
HLA-C*06:02
Where is the MHC causing all systemic rheumatic disease located?
Chromosome 6
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.
How do you treat Psoriasis?
Inhibit IL-17 and/or IL-23
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.
Briakinumab
Inhibits IL12 and IL-23
Treats Psoriasis
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
Low amounts of IL-17
Critical for epithelial integrity
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
Psoriasis
Affects ~3% of the population, hella common Mediated by CD8 T cells Infiltrate basal layers of skin Release cytokines Thwart normal keratinocyte maturation
Psoriasis Plaques
Itchy
Hypervascularized - The plaques bleed if you scratch them
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
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
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)
Transient Weak ANA positivity
Could be part of the polyclonal B cell activation of EBV infection. ANA positivity is common even without autoimmune diseases.
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
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
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.
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
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
If you see IgG autoantibodies
You know there is a T cell presiding over that B cell and telling it to try harder
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
Anti dsDNA Ab
Highly specific for SLE (>50 - 75%)
Anti ssDNA Ab
Very nonspecific. Everyone has this.
Anti-Histone Ab
Found in bout 30 - 40% of SLE patients
Found in >90% of drug (hydralazine)-induced Lupus
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
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
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
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
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
What are La and Ro proteins involved in doing?
Regulation of eukaryotic translation and transcription factor binding
Pro-inflammatory signals that enhance the response to immune complexes
Anti DNA/nucleoprotein complex binding to TLR9
Anti ribonucleoprotein-RNA complexes binding to TLR7
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
Smoking
High Relative Risk for most autoimmune conditions
