Transcript Immunopathology 2

ImmunoPathology II
Autoimmune Diseases
R. Pat Bucy, MD, PhD
Professor of Pathology, Microbiology, and
Medicine
Organ Specific and Non-Organ Specific
Autoimmune Diseases
Organ Specific
Localized to
Antigen
given organ
Non-Organ Specific
Widespread throughout the
body
Antigen in organ Immune Complex
Lesions is target of
deposition in many tissues
immune attack
– skin, joints, kidney
With other organ With other non-organ
Overlap
specific diseases specific diseases
Breaking Tolerance
Experimental Induction of anti-self responses
• Conjugation of self epitopes to immunogenic determinants
• Localization with another vigorous immune response
• Exposure of "Hidden" self antigens
• Genetic patterns of responsiveness
General Scheme
Induction of Organ Specific Autoimmune Disease
• Induction of local immune
response
– Infection, Drug Rx, Trauma, etc
• Malfunction of immune
regulation
– Genetic predisposition
• Progressive immune
response to tissue Ag
– Epitope Spreading
• Tissue destruction and loss
of function
Organ Specific Autoimmune Diseases
• Endocrine
– Thyroiditis/Grave's Disease
– Insulin Dependent Diabetes
– Atrophic Gastritis/Pernicious
Anemia
– Idiopathic Addison's Disease
– Idiopathic Hypoparathyroidism
– Idiopathic Hypogonadism
– Idiopathic Hypophysitis
• Neuromuscular system
– Multiple Sclerosis
– Guillian-Barre (Idiopathic
Polyneuritis)
– Myasthenia Gravis
• Gastrointestinal
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Crohn's Disease
Ulcerative colitis
Primary Biliary Cirrhosis
Chronic Active Hepatitis
• Miscellaneous
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Sjögren's Syndrome
Idiopathic myocarditis
Interstitial pneumonitis
Idiopathic Interstitial Nephritis
Lichen Planus
Bullous Skin Diseases
• Iatrogenic
• Joints
– Rheumatoid arthritis
– Relapsing Polychrondritis
– Allo-Transplant rejection
Multiple Sclerosis
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Immune Destruction of CNS Myelin
Histopathology - Depends on stage of lesion
Viral infection as Antecedent
Animal Models - EAE
Experimental autoimmune
encephalomelitis (EAE)
Insulin Dependent Diabetes Mellitus
Immune mediated destruction of Islet b cells
• Histopathology
• Epidemiology
– Viral Antecedent
– MHC linkage
• Animal Models
– BB rat
– NOD mouse
– low dose streptozoticin
Islets of Langerhans
Normal mouse
NOD mouse with acute
“insulitis”
Autoimmune Thyroiditis
• Lymphocytic (Hasimoto’s) Thyoiditis
– Chronic inflammatory lesion that results in destruction
of follicles and ultimately hypothyriodism
• Grave’s Disease
– Antibody to TSH Receptor that stimulates receptor
function and results in hyperthyroidism
Graves’ Disease
Myasthenia Gravis
• Muscle weakness due to autoantibody to
acetylcholine receptor of neuromuscular
junction
• Symptoms can be transferred with antibody
to AchR
• Relationship to the Thymus
Myasthenia Gravis
(Blocking auto-antibodies)
Inflammatory Bowel Disease
Two clinical entities with substantial overlap
• Crohn's Disease (Regional Enteritis)
– Transmural inflammation
– Occurs throughout GI tract, terminal ileum most
common
– "Skip lesions" and granulomas common
– Several new animal models
• Ulcerative Colitis
– inflammation restricted to mucosa
– involves contiguous areas in colon (may extend into
ileum)
Rheumatoid Arthritis
• Chronic inflammatory disease of joint
synovium
• Presence of Rheumatoid factor
– antibody to Fc of IgG usually of IgM class
– form immune complexes but rarely result in
glomerulonephritis
• Erosive lesions of cartilage and bone result
from inflammatory “pannus”
• Can involve other organs besides joints
• Occasionally associated with other
autoimmune syndromes
Rheumatoid Arthritis
Rheumatoid Nodule
Plasma cells in Rheumatoid synovitis
Rheumatoid Arthritis
Rheumatoid Arthritis
Synovial erosions
Systemic Lupus Erythematosis
• Classic “Systemic” Autoimmune Disease
• Mediated by immune complex injury
– DNA/anti-DNA immune complexes often implicated in
tissue injury
• Animals models - genetic predisposition to
immune complex formation and nephritis
• Variant forms of Lupus
Lupus Nephritis
A
B
C
D
E
Focal Proliferative GN
Diffuse Proliferative GN
“wire loop” lesions
Subendothelial IC
“Granular” pattern of IgG
Lupus skin Lesion
“butterfly” rash
General Scheme
Induction of Organ Specific Autoimmune Disease
• Induction of local immune
response
– Infection, Drug Rx, Trauma, etc
• Malfunction of immune
regulation
– Genetic predisposition
• Progressive immune
response to tissue Ag
– Epitope Spreading
• Tissue destruction and loss
of function
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
? Potential Hypersensitivity
auto-Ag
T cells
Memory
Time (days)
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
auto-Ag
T cells
Time (days)
auto-Ag
Regulatory T
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
? Potential Hypersensitivity
auto-Ag
T cells
Time (days)
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
auto-Ag
T cells
Time (days)
Autoimmune
Disease
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
? Potential Hypersensitivity
auto-Ag
T cells
Time (days)
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
auto-Ag
T cells
Time (days)
Infection and Hypersensitivity
anti-viral immune response
Activity
Tissue Injury
(auto-antigens)
Viral
infection
Contributors to control
auto-Ag •
T cells
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Time (days)
Dynamics of infectious
organism
Frequencies and function of
autoreactive T cells
Cytokine milieu - TGFb +
IL-10 versus IL-6, TNFa,
IFNg
Amount and kinetic course
of auto-Ag
Overview of ImmunoPathology
• Immune mechanisms that result in tissue injury
• Classification by mechanism vs antigen source
• Exogenous antigens
– Infectious Agents
– Environmental Agents
• Iatrogenic
– Solid organ transplants
– Bone marrow transplants
• Neoplastic cells
• Autoantigens
ImmunoPathology Lab Discussion
http://peir.path.uab.edu/iplab/