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INTRODUCTION
Self tolerance is lost
Specic adaptive immune responses
mounted against self antigens Inability to eliminate antigen leads to
cronic in!ammatory process
"rlic termed tis horror autotoxicus
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Autoimmune Diseases
Failure of autoantibodies and T cells torecognize own cells
Autoantibodies and T cells launch attackagainst own cells
Perhaps due to overactive or anoverabundance of helper T lymphocytes
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Examples of Autoimmune Diseases
Multiple sclerosis
Myasthenia gravis
Crohn’s disease
Grave’s disease
Type 1 Diabetes mellitus
Rheumatoid arthritis
PsoriasisScleroderma
Systemic lupus erythematosus
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Autoimmune diseases mediated
by cytoto#ic antibodies $Type II%
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Autoimmune diseases mediated
by immune comple#es $Type III%
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Autoimmune diseases
mediated by T&cells $Type I'%
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Autoimmune disease susceptibility
(enetic predisposition
› T)in studies $Diabetes* +,-
mono.ygotic vs/ 0- di.igotic%› 1amily studies
Association )it 23C genotype
›
34A genotyping
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Associationbet)een
34A andsusceptibility to
autoimmune disease
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Diagnosis: AutoimmuneDisease
Genetic predisposition
› coding for the variety of MHC molecules
Demographics› most common among middle aged women
Additional viral infections
Disease specific environmental factors Aging, stress, hormones, pregnancy
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Possible Causes:› Inefficient lymphocyteprogramming
› “Self proteins” circulate
without having been exposedto system(ex: sperm, eye lens, thyroid)
› Reactions between self-antigens and antibodyproduction against foreign
antigens
Potential Treatments:› Control inflammation
(ex: diabetes mellitus)
› Immunosuppressive Medication
(ex: corticosteriods,cyclosporin, methotrexate)
› Therapeutic Antibodies againstspecific T cell molecules
(with fewer side effects)
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S56gren7s Syndrome
Cronic autoimmune disorder
2a5or clinical manifestations resulting
from canges in e#ocrine glands
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1orms of S56gren7s
Syndrome
8rimary S56gren7s is caracteri.edby in!ammatory cell involvement ofbot te salivary and lacrimalglands
Secondary S56gren7s includes oter
dened connective tissue disease Causes are un9no)n
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1eatures of S56gren7s Syndrome
Glandular epithelial cells participate in the
autoimmune disease process
Epithelial cells produce a number ofimmunologically active mediators
May serve as antigen-presenting cells
Epithelial cell responses modulatemechanisms occurring in the salivary glands
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Is S56gren7s Syndrome anAutoimmune Disorder:
Described as an autoimmunee#ocrinopaty $Strand and Talal; ,%
(rouped )it oter connective tissuediseases
› Reumatoid artritis
› Systemic lupus erytematosis $S4"% ?at is te evidence tat it is an
autoimmune disease:
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"vidence tat S56gren7s Syndrome
is an Autoimmune Disease
A specic auto&immunogen andpatogenic antibodies ave not been
identied Autoantibodies tat ave been found
ave not been so)n to ave any directpatogenic e@ects on e#ocrine tissues
Tere is substantial circumstantialevidence tat tissue damage is te resultof autoimmunity
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8olyclonal 3ypergammaglobulinemia
&cell yper&responsiveness
2ar9ed elevations of Ig( 8roduction ofreumatoid factors
8resence of anti&nuclear antibodies› "#tractable nuclear antigens Anti&SS&A $Ro% and anti&
SS& $4a%
Antibodies are found directed against salivary
duct cells $=,- of patients%› 8rimarily against e#tractable nuclear antigens
› Concentration does not correlate )it glanddestruction
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Oter Caracteristics
"levated sedimentation rates anddecreased ?C counts; as seen in oterautoimmune connective tissue diseases
Specic e#tended 23C aplotype at aiger freBuency tan controls
23C&encoded proteins›
Induction of tolerance to self proteins› Selection of te T&cell repertoire
› inding and presentation of antigen to T&cells
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3istopatology
2ononuclear inltrate consistingprimarily of T&cells $primarily CD%
3ost of mediators
Altered cell adesion moleculese#pression
Increased 34A class II antigens
e#pression Immunosuppressive terapy often
e@ective
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Classical 3istopatological4esion
4ympo&epitelial lesion a@ecting te parotidgland
8rogressive replacement of te salivary tissue
by dense lympoid inltrates 1ormation of proliferating islands of ductal
epitelial cells
Creates )ell&formed lympoid follicles typical
of 2A4T and may give rise to lympomas of te2A4T type as an e#pansion of monoclonal &cells
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Salivary(landStructure
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Scleroderma(Systemic Sclerosis)
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Defnition
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Epidemiology
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Classifcation
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Classifcation o systemic sclerosis
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Classification of systemic
sclerosis
Classification of systemic
sclerosis
2. Limited cutaneous systemic sclerosis
1) symmetric restricted fibrosis
- affecting the distal extremities and face/neck
2) prolonged delay in appearance of distinctive internal
manifestation 3) prominence of calcinosis and telangiectasia
) good prognosis
! "#$%& syndrome
- calcinosis' #aynaud(s phenomenon' esophageal dysmotility' sclerodactyly' telangiectasia
2. Limited cutaneous systemic sclerosis
1) symmetric restricted fibrosis
- affecting the distal extremities and face/neck
2) prolonged delay in appearance of distinctive internal
manifestation 3) prominence of calcinosis and telangiectasia
) good prognosis
! "#$%& syndrome
- calcinosis' #aynaud(s phenomenon' esophageal dysmotility' sclerodactyly' telangiectasia
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Classifcation o systemicsclerosis
Overlap syndromes
– 1eatures of systemic sclerosis togeter)it tose of at least one oter
autoimmune reumatic disease; e/g/ S4";RA; or polymyositis
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"tiology
"nvironmental factors % 4&tryptopan =% silicone implant $:%
(enetic predisposition Defective immunoregulation ; cyto9ines
+% umoral immunity–
ypergammaglobulinemi
a
– autoantibody
production
– antinuclear antibody
$% J =0-
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PathogenesisPathogenesis
%usceptible host
$xogenous events
mmune systemactivation
$ndothelial cell
activation/damage*ibroblast activation
$nd stage pathology
+bliterative
vasculopathy
*ibrosis
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Pathogenesis
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Clinical eatures
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Raynaud7s penomenon
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Raynaud7s penomenon
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Raynaud7s penomenon
. Arteriogram
& narro)ing and
occlusion
of digital arteries
& pro#imal vessels;
arcades
and metacarpalvessels are
)idely patent
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Telangiectasia
. local disruption of
angiogenesis
. blanced by pressure
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Clinical featuresClinical features
2. %kin involvement ,1)
1) stage
- edematous phase
- indurative phase
- atrophic phase
2) firm' thickened bound to underlying soft tissue
3) decrease in range of motion' loss of facial expression' inability
to open mouth fully' contractures
2. %kin involvement ,1)
1) stage
- edematous phase
- indurative phase
- atrophic phase
2) firm' thickened bound to underlying soft tissue
3) decrease in range of motion' loss of facial expression' inability
to open mouth fully' contractures
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"dematous pase
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S9in Induration
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Acrosclerosis
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1acial canges
&ight' thin lips ith vertical perioral furros
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Clinical featuresClinical features
2. %kin involvement ,2)
ulceration' loss of soft tissue of finger tip' pigmentation' calcific
deposit' capillary change
3. usculoskeletal system
• olyarthritis and flexion contracture
• uscle eakness and atrophy ,primary /secondary)
2. %kin involvement ,2)
ulceration' loss of soft tissue of finger tip' pigmentation' calcific
deposit' capillary change
3. usculoskeletal system
• olyarthritis and flexion contracture
• uscle eakness and atrophy ,primary /secondary)
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Terminal digit resorption
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Acrolysis
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Digital pitting scars
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Calcinosis and acrolysis
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Clinical featuresClinical features
. intestinal involvement
1) esophagus0 hypomotility and retrosternal pain'
reflux esophagitis' stricture
2) stomach0 delayed emptying
3) small intestine0 pseudo-obstruction' paralytic ileus'
malabsorption' eight loss' cachexia
) large intestine0 chronic constipation and fecal impaction
diverticula
. intestinal involvement
1) esophagus0 hypomotility and retrosternal pain'
reflux esophagitis' stricture
2) stomach0 delayed emptying
3) small intestine0 pseudo-obstruction' paralytic ileus'
malabsorption' eight loss' cachexia
) large intestine0 chronic constipation and fecal impaction
diverticula
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Abnormal motility
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Diverticula
. arium enema study
& multiple )ide&
mouted
diverticula of colon
& broad base and
nec9
& usuallyasymptomatic
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Diverticula
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Clinical featuresClinical features
. lungs
1) 2/3 of patients affected
- leading cause of mortality and morbidity in later stage
of systemic sclerosis
2) pathology
- interstitial fibrosis
- intimal thickening of pulmonary arterioles
,pulmonary hypertension)
3) "omplains - dry cough' breathlessness
. lungs
1) 2/3 of patients affected
- leading cause of mortality and morbidity in later stage
of systemic sclerosis
2) pathology
- interstitial fibrosis
- intimal thickening of pulmonary arterioles
,pulmonary hypertension)
3) "omplains - dry cough' breathlessness
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8ulmonary brosis
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Clinical featuresClinical features
. heart ,14)
1) pericarditis
2) heart failure
3) arrhythmia
) myocardial fibrosis
. heart ,14)
1) pericarditis
2) heart failure
3) arrhythmia
) myocardial fibrosis
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Clinical featuresClinical features
5. kidney
1) diffuse scleroderma in association ith
rapid progression of skin involvement
2) pathology
- intimal hyperplasia of the interlobular artery - fibrinoid necrosis of afferent arterioles
- glomerulosclerosis
3) proteinuria' abnormal sediment' a6otemia'
microangiopathic hemolytic anemia' renal failure
5. kidney
1) diffuse scleroderma in association ith
rapid progression of skin involvement
2) pathology
- intimal hyperplasia of the interlobular artery - fibrinoid necrosis of afferent arterioles
- glomerulosclerosis
3) proteinuria' abnormal sediment' a6otemia'
microangiopathic hemolytic anemia' renal failure
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Midney arteriogram
Midney Intimal arterial
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Midney; Intimal arterialbrosis
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Clinical eatures
"#ocrine glands
– erostomia
– #eroptalmia
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Laboratory fndings
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Diagnosis
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TreatmentTreatment
7 ide spectrum of clinical manifestations and severity- spontaneous improvement occurs fre8uently
• 9isease modifying interventions ,:)
- penicillamine
- methotrexate- immunosuppressive agent0 cyclosporin' *;-γ
- recombinant human relaxin
• %ymptomatic ,organ-specific) treatment
7 ide spectrum of clinical manifestations and severity- spontaneous improvement occurs fre8uently
• 9isease modifying interventions ,:)
- penicillamine
- methotrexate- immunosuppressive agent0 cyclosporin' *;-γ
- recombinant human relaxin
• %ymptomatic ,organ-specific) treatment
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Treatment
Raynaud7s penomenon and iscemia
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TreatmentTreatment
ulmonary
1) nterstitial fibrosis
- corticosteroid
- cyclophosphamide' a6athioprine
2) pulmonary artery hypertension
- calcium channel blocker
- prostacyclin
- transplantation
ulmonary
1) nterstitial fibrosis
- corticosteroid
- cyclophosphamide' a6athioprine
2) pulmonary artery hypertension
- calcium channel blocker
- prostacyclin
- transplantation
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Treatment
Renal
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Prognosis