autoimmune disease of connective tissue and the …...what is autoimmunity? autoimmunity –presence...
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Path2220 INTRODUCTION TO HUMAN DISEASE
AUTOIMMUNITY
Dr. Erika BosioResearch Fellow – Centre for Clinical Research in
Emergency Medicine,
Harry Perkins Institute of Medical Research
University of Western Australia
2017
OBJECTIVES
Aims of this lecture:
– To illustrate the spectrum of autoimmune diseases
– To define pathogenic aspects of autoimmunediseases
– To use SLE as model a model of systemic autoimmunity
– To use thyroid disease as a model of organ-specific autoimmunity
What is Autoimmunity?
Autoimmunity – presence of auto-antibodies and/or
self-reactive T cell responses. Only when these
responses cause clinical abnormality is an
autoimmune disease present.
Hashimoto’s ThyroiditisSystemic Lupus Erythematosus
(SLE)
ACTIVATION OF T AND B CELL RESPONSES
T- AND B-CELL
INTERACTION
How does the body control self-reactivity?
IMMUNOLOGICAL
TOLERANCE
Lack of response of T- or B-cells to antigen
exposure:
•Central and peripheral tolerance
•Principal mechanisms
Clonal deletion of self reactive lymphocytes
Tolerance due to clonal anergy
Tolerance caused by lack of communication
Suppression of self-responses
IMMUNOLOGICAL
TOLERANCECentral (Intrathymic) Mechanisms of Tolerance :
Immature T-cells migrate from bone marrow to thymus
Interact with self peptide-MHC complexes on thymic epithelium
Double positive (CD4+/CD8+) thymocytes develop T-cell receptors (TCRs) – Only those with low affinity for self-antigens persist (Positive Selection)
Cells with dysfunctional TCRs or with very high or no affinity for MHC-self peptide complex undergo apoptosis (Negative Selection)
Positively selected cells then lose either CD4 or CD8 and leavethymus to function in periphery as mature CD4+ or CD8+ T-cells
Adapted from Walker, LSK, Abbas, AK [2002] Nat. Rev. Immunol. 2:11
IMMUNOLOGICAL
TOLERANCE
Peripheral (Non-thymic) Mechanisms of
Tolerance : • Peripheral T cell tolerance can be regulated by antigen
presenting cells and the positive and negative
regulatory receptors expressed on T cells.
• CD28 ligation co-stimulatory
effects
• CTLA-4 inhibitory effects (Tregs)
• The balance of CD28 and CTLA-4 derived
signals is critical to T cell activation and
tolerance.
• Regulatory T cells can effect the functional inactivation
of otherwise competent T cells
IMMUNOLOGICAL
TOLERANCE
Tolerance by Immune Suppression – Treg
cells
AUTOIMMUNE DISEASE
• When the mechanisms
controlling and maintaining
tolerance function poorly or
breakdown, autoimmunity
and autoimmune disease can develop
• Mechanism: Unclear
Probably multifactorial
Drugs
Viral illness
• Most associated with autoantibodyproduction
• Some due to cell mediated immune (CMI) responses
THE AETIOLOGY OF AUTOIMMUNITY
Induction of Autoimmunity -
1. Cooperation between autoreactive B-cells
and non- autoreactive T-cells
• Autoreactive B-cells - Efficient antigen presenting cells (APCs). May present antigen to non-autoreactive T-cells
• Part of the cross-reactive antigen has an epitope that normal (non-autoreactive) T cells recognise. This processed antigen is now capable of stimulating T-cells and provides “help” for autoreactive B cells
THE AETIOLOGY OF AUTOIMMUNITY
Induction of Autoimmunity
-
2. Molecular Mimicry
T-cells may be induced toprovide help aftercoming into contact witha microbial epitopewhich cross-reacts withself-antigens
3. Modification of autoantigen
The administration of drugs or defects in synthesis could result in the modification of a previously tolerised epitope, rendering it antigenic
Not commonly reported
• Autoimmune hemolytic anaemia following treatment with -methyldopa
• Isoniazid may produce arthritis, associated with production of anti-nuclear antibodies
• Procainamide induces anti-nuclear antibodies in a high proportion of patients, with 40% showing clinical signs of SLE
Th
T/B
Antigen
on APC
surface
Th
THE AETIOLOGY OF AUTOIMMUNITY
Autoimmunity
• Autoimmune disease usually arises spontaneously and persists, leading to long term damage.
• Can be Organ-Specific such as Hashimoto’s thyroiditis with organ-specific autoantibodies
• Or: the lesions are localised to a single organ but the autoantibodies are not organ-specific eg Primary Biliary Cirrhosis
• Or Non-Organ Specific diseases, where lesions and auto-antibodies are not confined to any one organ e. g. rheumatological disorders such as Systemic Lupus Erythematosus (SLE)
Organ-specific
Non organ-specific
Hashimoto’s thyroiditisprimary myxoedemathyrotoxicosispernicious anaemiaAddison’s diseaseT1DGoodpasture’s syndromemyasthenia gravispemphigoidmultiple sclerosis (?)autoimmune haemolytic anaemiaidiopathic thrombocytopenic purpuraidiopathic leucopeniaprimary biliary cirrhosisactive chronic hepatitis (HBsAgnegative)ulcerative colitisSjögren’s syndromerheumatoid arthritisdermatomyositissclerodermamixed connective tissue diseasesystemic lupus erythematosus
Either Antibody or T-Cells Can Cause Tissue Damage in Autoimmune
Disease
T-Cells Specific for Self Antigens Can Cause Direct Tissue Injury and Playa
Role in Sustained AutoantibodyResponses
AUTOIMMUNE DISEASE
Systemic - A response against auto-antigens not restricted to single organ
DISEASE AUTOANTIGEN
Systemic lupus
erythematosue (SLE)
Nuclear antigens
Cellular cytoplasmic antigens
PhospholipidsRed blood cell and platelet antigens
Rheumatoid Arthiritis Immunoglobulin
Sicca syndrome
(Sjögren’s syndrome)
Components of exocrine glands
Nuclear antigens – especially anti-Ro
(SSA) and anti-La (SSB)
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
• Chronic multi-system inflammatory disorder
• Unknown aetiology
• Occurs predominantly in females (10:1)
• Spectrum of clinical course:
Mild Severe
May be fatal
• It is associated with:
- Uncontrolled interaction between T and B cells - Polyclonal B-cell activation
- Anti-nuclear antibodies (ANA)
- Probable defects in regulationof B-cells +/- T-cells
IMMUNOPATHOGENESIS OF SLE
Predisposition to develop SLE appears to be multi-factorial
There is a strong genetic basis
The development of SLE is a multi-step process
Hallmark -
The production of anti-nuclear antibodies - ANA’s
ANA’s are IgG autoantibodies directed against nuclear antigens
The presence of numerous auto-antibodies, particularly ANA’s
due to
and
- breakdown in immune surveillance
- loss of self tolerance
Hep-2 Cells
Add Patient’s Serum
Anti-nuclear IgG (ANA) in Patient’s Serum Binds to Nucleus
DETECTION OF ANA IN PATIENT’S SERUM
Fluorescein LabelledAnti-IgG Detects ANA
Add Fluorescein-Labelled
Anti-IgG
PATTERNS OF ANA BY IIF
Homogeneous Anti-DNA-histonecomplex (SLE,
drug- induced
lupus)
Anti-proteins of
nuclear envelope (Predominantly in
SLE)
Rim/Peripheral
Anti-antigens in thenucleus (the ENAs)(SLE, DL, MCTD, SS,
Scleroderma)
Speckled Anti-RNA Polymerase(predom. in
Scleroderma)
Nucleolar
ANA IN HEALTH AND NEWLY DIAGNOSEDSLE
A positive ANA test is NOT specific for SLE or any other connective tissue disease
Negative ANA or ANA at low dilution – 1:40 –Excludes SLE
< 2.5 2.5 105 15
HEALTH (196)
SLE (45)
Cu
mu
lati
ve f
req
ue
ncy
(%)
7.5
1:40
> 30
1:2560
20 30
1:12801:320
100
9080
70605040
3020100
ANA IU/ml
TITRE
ANA TITRE 1:40 1:320
Frequency in Heathy 32% 2%
Sensitivity for Diagnosis of SLE 97% 87%
Specificity for Diagnosis of SLE 68% 95%
KEY CONCEPTS OF SLE
Autoantibodies Mediate Pathology of SLE
By binding to cell surface antigens
Red blood cells - Haemolytic anaemia Platelets - Autoimmune thrombocytopenia Neutrophils and lymphocytes - Leukopenia Neuronal cells - Diffuse CNS disease
Direct Coomb’s Test
Used to detect the
presence of IgG or C3
bound to RBC’s
KEY CONCEPTS OF SLE
Autoantibodies Mediate Pathology of SLE By forming immune complexes that are then deposited in
tissues and interfere with function or cause tissue
damage by complement activation
DNA-anti-DNA Lupus nephritis Vasculitis? – arthritis
? – pneumonitis
By poorly understood mechanisms of disease association
Anti-phospholipid – Thrombosis(? inhibition of anticoagulant pathways)Anti-SS-A/Ro – Photosensitivity / rash / neonatal lupus
AUTOIMMUNE DISEASE
Organ Specific - A response against auto-antigens presentin single organ or system
DISEASE AUTOANTIGEN
Grave’s Disease TSH receptor of thyroid
Myasthenia GravisAcetyl choline receptor of skeletal
muscle
Diabetes Mellitus Components of pancreatic islet cells
PemphigusIntercellular substance of epidermis
and mucosal stratified epithelium
ORGAN-SPECIFIC AUTOIMMUNITY:THYROID AUTO-IMMUNE DISEASE
THYROID AUTO-IMMUNE DISEASE
Relatively common
1-2% of UK and USA populations
Subclinical disease in ~ 15%
Two categories:
a) Hyperthyroidism -
b) Hypothyroidism -
Grave’s disease
Hashimoto’s thyroiditis
Primary hypothyroidism
GRAVE’S DISEASE
Commonest cause ofhyperthyroidism
Peak incidence- 3rd and 4th decades
0.1 - 0.5% of population
Predisposing factors:
Living in areas of high iodine intake
Being female (F : M = 7 : 1)
PATHOGENESIS OF GRAVE’S DISEASE
1. Thyroid Stimulating Hormone (TSH) Receptor Antibodies (Thyroid Stimulating Immunoglobulins(TSI))
IgG
Compete with TSH for receptor binding
Stimulate glandular function ---> Hyperthyroidism
Titre correlates well with severity
Can cross placenta - Neonatal hyperthyroidism
2. Dense lymphocytic infiltrate -
Autoreactive CD4+ T-cells
?? Help B-cells to produce
autoantibodies
Normal Thyroid
PATHOGENESIS OF GRAVE’S DISEASE
HASHIMOTO’S THYROIDITIS
• Chronic inflammatory disease of
thyroid -autoimmune factors play
a prominent role
• Incidence - ~ 0.5% in general
population
• Peaks - Middle age
F >> M (20:1)
HASHIMOTO’S THYROIDITIS
• Evidence of participation of autoimmune factors:
• Lymphocytic infiltration of the gland
• Increased concentrations of immunoglobulins and antibodies against several components of thyroid tissue
• High titre of anti-Thyroid Peroxidase antibody
• Almost always present
• Also occur in other thyroid disorders, such as Graves' disease, but with lesser frequency
• In pregnant women, may be associated with higher risk for miscarriage, independent of the thyroid status
PATHOGENESIS OF HASHIMOTO’S THYROIDITIS
1. Dense lymphocytic infiltrate -
CD4+ and CD8+ T-cells
Macrophages, plasma cells
20 lymphoid follicles
and germinal centres
Possibility of strong T-cell mediated
cytotoxic reactions
CD4+ T-cells may help B-cells toproduce anti-thyroid autoantibodies
PATHOGENESIS OF HASHIMOTO’S THYROIDITIS
2. Autoantibodies
Antigens may be exposed on surface of thyroid follicular cells
3. Complement fixation - IgG autoantibodies
4. Antibody-dependent cytotoxicity
HASHIMOTO’S THYROIDITIS AUTOANTIBODIES
Two main autoantibodies
1. Anti-thyroid peroxidase (TPO)
2. Anti-thyroglobulin (TG)
Not 100% specific for Hashimoto’s thyroiditis
Valuable exclusionary test in patients with thyroid disease
• > 98% with thyroiditis have one or both of theseantibodies
• A negative result excludes diagnosis of thyroiditis
MECHANISM OF AUTOIMMUNITY IN HASHIMOTO’S THYROIDITIS
Current Genomics, 2011, 12, 576-
588
1. Anti-thyroid peroxidase(Anti-microsomal)
High titre in circulation and
apical border of thyroid cell
Two possible roles:
a) Kill thyroid cells in
presence of complement
b) Bind to and interfere with
function of peroxidase
HASHIMOTO’S THYROIDITISAUTOANTIBODIES
2. Anti-thyroglobulin Unlikely to have pathogenic roleUsually in low titre Do not appear to fix complement
Autoantibodies to Receptors Alter Receptor Function,
Causing Disease:
Stimulating (Hyperthyroidism) or Blocking (Hypothyroidism)