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ImmunoPathology IIAutoimmune Diseases
R. Pat Bucy, MD, PhDProfessor of Pathology, Microbiology, and
Medicine
Organ Specific and Non-Organ Specific Autoimmune Diseases
Organ Specific Non-Organ Specific
AntigenLocalized to given organ
Widespread throughout the body
LesionsAntigen in organ is target of immune attack
Immune Complex deposition in many tissues – skin, joints, kidney
OverlapWith other organ specific diseases
With other non-organ specific diseases
Breaking ToleranceExperimental 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 SchemeInduction 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
• Joints– Rheumatoid arthritis– Relapsing Polychrondritis
• Gastrointestinal– Crohn's Disease– Ulcerative colitis– Primary Biliary Cirrhosis– Chronic Active Hepatitis
• Miscellaneous– Sjögren's Syndrome– Idiopathic myocarditis– Interstitial pneumonitis– Idiopathic Interstitial Nephritis– Lichen Planus– Bullous Skin Diseases
• Iatrogenic– Allo-Transplant rejection
Multiple Sclerosis
• 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 MellitusImmune 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 DiseaseTwo 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 ArthritisSynovial 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 Focal Proliferative GNB Diffuse Proliferative GNC “wire loop” lesionsD Subendothelial ICE “Granular” pattern of IgG
Lupus skin Lesion
“butterfly” rash
General SchemeInduction 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
Time (days)
Act
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y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
? Potential Hypersensitivity
Infection and Hypersensitivity
Memory
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
auto-AgRegulatory T
Infection and Hypersensitivity
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
? Potential Hypersensitivity
Infection and Hypersensitivity
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
AutoimmuneDisease
Infection and Hypersensitivity
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
? Potential Hypersensitivity
Infection and Hypersensitivity
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
Infection and Hypersensitivity
Time (days)
Act
ivit
y
anti-viral immune response
Viralinfection
Tissue Injury(auto-antigens)
auto-AgT cells
Contributors to control
• 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
Infection and Hypersensitivity
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
