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Autoimmunity andConnective Tissue
DiseaseDr Alexander Fraser
consultant rheumatologist
University Hospitals Limerick2014
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Aims of talk
Overview of autoimmunity
Overview of CTDparticularly SLE
Highlight clinical significance
Characteristic features
Methods of detection
Treatments
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AUTOIMMUNITY
Diagram adapted from Immunology for Medical students Nairn and Helbert
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IMMUNE SYSTEM
One of the central dogmas of immunity is thatthe immune system does not react against self
and can distinguish between
self and non-self
Nature provides an intriguing exception to therule of self-non self recognition in thephenomenon of Autoimmunity.
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SELF TOLERANCE MECHANISMS
How does the immune system make itself unresponsive to self antigens?The immune system has evolved self tolerance mechanisms.
During maturation in the thymus, T cells displaying self MHC and peptidereactive TCRs of a certain affinity/avidity are maintained and propagated
within the thymus.
Those T cells exhibiting receptors of dangerously high affinity/avidity areeliminated or inactivated. (negative selection).
During B cell development and maturation, cells reactive with membranebound self antigens or soluble key antigens are eliminated or inactivated.
Therefore through these editing processes a state of self tolerance is
induced. Peripheral tolerance also need to be maintained
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TOLERANCE
Controlled unresponsiveness
Immunological Self tolerance
Controlled inability to respond to self, despite
having the capability to do so
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AUTOIMMUNITY
However not all self reactive lymphocytes are deleted during T and B cellmaturation,
Therefore POTENTIALLY SELF REACTIVE CELLS EXIST IN THEBODY.
The activity of these autoreactive T and B cells must be regulated byCLONAL ANERGY or CLONAL SUPRESSION
Sometimes there is a breakdown in the maintenance of SELFTOLERANCE, A FAILURE TO DISCRIMINATE SELF FROM NONSELF and this leads to:
An autoimmune response characterized by activation of self reactive
clones of B and T cells generating Humoral and cell mediated responsesagainst self antigen.
This leads to AUTOIMMUNITY
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Autoimmunity:
Some autoimmunity is normal. Most healthy individuals produce some
autoantibodies--usually very low levels
Natural antibodies: Secreted by a special subset of B1 cells, without T help or
genetic changes
Bind a range of antigens with low affinity, auto antibodies
remove the products of tissue breakdown
eg collagen by anti-collagen antibodies.
In the gut lining, available to bind invading gut bacteria
Bind DNA released from apoptotic cells and other
cellular debris
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AUTOIMMUNITY
AUTOIMMUNITYimmune reaction to self components in the absenceof overt disease is much more common.
Indeed all of us have the capacity to mount autoimmune responses and insome circumstances this may be a physiological reaction. We all have
autoantibodies to an extent.
The fact that auto reactivity in the vast majority of cases does not lead todisease suggests that regulatory mechanisms are essential.
The state of balanced physiological autoimmunity may be described astolerance.
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AUTOIMMUNITY
Loss of immunological tolerance to selfcomponents
Autoimmune disease
Loss of immunological tolerance to selfcomponents, associated with pathology
Disease associated by one or moremanifestations of autoimmunity ie T or B cell
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AUTOIMMUNE DISEASE
Autoimmune disease is widespread, occurring in5-7% of the adult population in Europe andAmerica.
2/3 are female many with more than oneautoimmune disease
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Autoimmune diseases can be dividedinto two broad but overlappingcategories:
Organ specific
non-organ specific (systemic)
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Graves disease
Stimulates hormone synthesis
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Myasthenia GravisFunction blocked by autoantibodies
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Insulin dependent diabetes mellitisTissue changes
Adapted from Immunobiology, Janeway, Travers, Walport and Shlomchik,Garland Publishing 2001
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Non Organ specific (systemic) autoimmune disease:
The response is directed towards a broad range of targetorgansand
involves a number of organs and tissues.
A generalize defect in immune regulation results in hyperactive B and Tcells
Tissue injuryand inflammation occur in multiple sites in organs without
relation to their antigen make up.
Injury is usually initiated by vascular leakage and tissue deposition of
circulatory immune complexes.Immune complexes are formed by autoantibody responses to ubiquitous
soluble cellular antigens of nuclear origin or less commonly cytoplasmic
origin.
Therefore tissue damage is widespreadboth from CMI response and
direct cellular damages caused by auto antibodies and accumulation ofimmune complexes.
Non Organ specific - SLE
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An autoimmune diseases of connective tissue, inflammation and the
immune response may result in connective tissue damage, not only in and
around joints but also in other tissues such as the kidneys and brain.
Diagnosis is based on its particular symptom pattern, the findings during a
physical examination, and the results of laboratory tests. Sometimes the
symptoms of one disease overlap with those of another, in this case, the
disorder may be called undifferentiated connective tissue disease or
overlap disease.
CTD
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CTD
Activation of phagocytic cells
Tissue damage leading to release of more
nucleoprotein-complexes which in turn produce morecomplexes
Eventually inflammation induced in small blood
vessels, esp. kidney and brain.
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Connective Tissue Diseases
Main diseases SLE
Systemic sclerosis
Dermato/polymyositis Sjorgrens
Raynauds
Behcets Syndrome Often overlap (eg MCTD)
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Systemic lupus erythematosus
Chronic, inflammatory, multi-system, heterogenous,
relapsing and remitting course and prognosis
F>M (8:1), Child bearing age (20-40yrs)
Prevalence
1:2000 Europeans
1: 400 African-Americans; Asians
Genetics
HLA B8, DR2, DR3
60% concordance in MZ twins
Drugs: Hydralazine, phenytoin, procainamide,
isoniazid, penicillamine, minocyline, anti-TNF
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SLE: pathophysiology
Autoimmune
Excess Ab production: cytotoxic andimmune complex
Microvascular inflammation
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Common presentations
General malaise
Fatigue - most common
Fever Loss of weight
Serositis (pericarditis, pleuritis, peritonitis)
Polyarthritis (peripheral, symmetrical) Cutaneous features (photosensitive-20%)
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Malar rash
Flat
Often painful or itchy Worse in sunlight
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Discoid rash
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Annular variety
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Other rashes
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Subacute cutaneous
lupus
wax and wane
non scarring
non fixed
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Plantar-palmar erythema
and desquammation
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Alopecia: frontal
or diffuse
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Phalangeal involvement
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Mechanics hands
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Vasculitic lesions: painful
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Skin Biopsy
Biopsy of unaffected skin
Immune complexes and complement atdermo-epidermal junction
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Often painless mouth ulceration
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Arthropathy
Jaccouds - 10%
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Pleural effusion commonest
alveolitis/ fibrosis - uncommon
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50 % pts with lupus
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Direct Immunofluorescence
Detection of Immune complexes on
tissue biopsy from patient.Tissue sections eg skin, renal mounted
onto slides
Incubated with anti-human IgG-FITC
which binds to the IgG from the IC.
Lumpy bumpy pattern seen on renal biopsy
from lupus patient, ICxes on basement membrane
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Low
complementC3/C4
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Treatment of lupus
Skin/ Joints
Sunblock
Avoidance of sun
NSAID
HCQ
Mepacrine, thalidomide,
cyclosporin A
Minor organ
PrenisoloneAzathioprine
MTX
CyA
Mycophenolate
Life threatening
(renal or CNS)
IV MP and
cyclophosphamide
B Cell Depletion
plasma exchange
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Prognosis of SLE
Varies between individuals
5 yr survival > 90%
Worse if renal disease and CNS involvement
Atherosclerosis and increased lipids
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Polymyositis/ Dermatositis
Uncommon
ANA 40-50 %, Jo-1 antibody
Malignancy 25% adults (adenocarcinomas)
proximal muscle weakness
raised CK (ie not PMR)
abnormal EMG
Muscle biopsy
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Dermatomyositis
Heliotrope rash - eye lids MCPJ erythematous -Gottrons papules
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Treatment of polymyositis
Prednisolone
Methotrexate/ azathioprine
IV immunoglobulins/ B Cell Depletion
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Raynauds
Common
Idiopathic or secondary associated with
CTDsVasospasm
White (vasospasm)
Blue (hypoxia)
Crimson/red (hyperaemia,vasodilation)
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Raynauds Syndrome
Primary - benign
Secondary - pathology
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Treatment of Raynauds
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Treatment of Raynauds
Stop smoking
Keep warm and avoid cold (gloves, thermals)
Vasodialtors eg nifedipine
Sympathectomies - short term
Iloprost (prostacyclin)- digital ulcers or
ischaemia
Bosentan
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Anti-phospholipid syndrome
Primary
Secondary eg SLE
Anti-cardiolipin antiobodies, lupus anticoagulant Thrombosis - venous and arterial
Recurrent miscarriages
Thrombocytopaenia Other eg livedo reticularis, neurological disorders
Treatment: aspirin, warfarin, immunosupression
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Sjorgrens syndrome
Dry eyes and mouth
Primary or secondary associated with
connective tissue disease
Primary
Ro and La antibodies, RF +
Lungs
Renal tubular acidosis
Treatment eye drops, artificial saliva
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Parotid
enlargement
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Rose Bengal stain
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Schirmers test
10 mm in 3 min
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Sialogram
d
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Scleroderma
CREST syndrome
Skin Thickening
Calcinosis
Raynauds
Difficulty Swallowing
Telangiectasia
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B h S d
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Behcets Syndrome
Oral and Genital Ulceration
Eye Inflammation
Rashes
Vascular Occlusions
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Wegners
Granulomatosisis made on the basis of clinical features, the presence of raisedc-ANCA titers, and histopathologic confirmation.
ACR criteria for the diagnosis of WG:
Oral ulcers or nasal dischargeAbnormal chest radiography (nodules, fixed infiltrates, orcavities)Microhematuria (>5 red blood cells per high power field) or redcell casts in urine sediment (Klippel, 2001)Granulomatous inflammation on biopsy
They associated 2 of 4 positive criteria with a sensitivity of88.2% and a specificity of 92% (Leavitt, 1990). Diagnosis maybe difficult in early stages when the disease is localized.
C 1
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Case 1
Meds: Imdur, Aspirin, Atenolol
SHx: Lived with wife, 3 children, Ex-Smoker 2years
SR: Nasal stuffiness x 6 months.
OE: BP 145/95 T =N
Looked Well
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Case 2
Pr ntin C pl int
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Presenting Complaint
BC a 24 yr old male p/c to St Johns Hospitalon 7 August with
1. Right facial swelling
2. Hearing loss
3. Non healing skin lesion on left arm
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Clinical Improvement
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Clinical Improvement
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Conclusion
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Conclusion
Uncommon group of disorders
High associated morbidity and mortality
Early diagnosis and treatment
