ImmunoPathology I
R. Pat Bucy, MD, PhD
Professor of Pathology, Microbiology, and
Medicine
Type I Hypersensitivity
(AKA: Anaphylactic type, immediate hypersensitivity)
• Due to activity of IgE
• Cross-linkage of Fce resulting in mast cell
degranulation
• Anaphylaxis - local vs systemic
• Skin test peaks in ~10 minutes
• Normal function of IgE
Immediate Hypersensitivity (Type I)
Type II Hypersensitivity
(AKA: Antibody mediated cytotoxic type)
• Ab coating of cells → phagocytosis & ADCC
• Ab + complement → direct lysis
• Ab interaction with cell surface receptor →
activation or inhibition of bioactivity
Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Disease
Autoimmune hemolytic
anemia
Autoimmune
thrombocytopenic
purpura
Pemphigus vulgaris
Target Antigen
Erythrocyte membrane proteins
(Rh blood group antigens, I
antigen)
Platelet membrane proteins
(gpllb:Illa integrin)
Clinicopathologic
Mechanisms of Disease
Manifestations
Opsonization and phagocytosis Hemolysis, anemia
of erythrocytes
Opsonization and phagocytosis Bleeding
of platelets
Proteins in intercellular junctions
of epidermal cells (epidermal
cadherin)
Vasculitis caused by
Neutrophil granule proteins,
ANCA
presumably released from
activated neutrophils
Goodpasture syndrome Noncollagenous protein in
basement membranes of kidney
glomeruli and lung alveoli
Acute rheumatic fever
Streptococcal cell wall antigen;
antibody cross-reacts with
myocardial antigen
Antibody-mediated activation of Skin vesicles (bullae)
proteases, disruption of
intercellular adhesions
Neutrophil degranulation and
Vasculitis
inflammation
Myasthenia gravis
Acetylcholine receptor
Graves disease
(hyperthyroidism)
Insulin-resistant
diabetes
Pernicious anemia
TSH receptor
Insulin receptor
Intrinsic factor of gastric parietal
cells
Complement- and Fc receptormediated inflammation
Nephritis, lung hemorrhage
Inflammation, macrophage
activation
Myocarditis, arthritis
Antibody inhibits acetylcholine
binding, down-modulates
receptors
Antibody-mediated stimulation
of TSH receptors
Antibody inhibits binding of
insulin
Neutralization of intrinsic factor,
decreased absorption of vitamin
B12
Muscle weakness, paralysis
Hyperthyroidism
Hyperglycemia, ketoacidosis
Abnormal erythropoiesis,
anemia
Type III Hypersensitivity
(Immune complex type)
• Immune complex physical chemistry
and IC deposition
• IC deposition in vessel walls and
glomeruli
– complement deposition and neutrophil
activation
• Skin test peaks in ~10 hours
– Skin test called Arthus reaction
Examples of Immune Complex-Mediated Diseases
(Type III Hypersensitivity)
Clinicopathologic
Manifestations
Nephritis, skin lesions,
arthritis, others
Disease
Systemic lupus
erythematosus
Antigen Involved
Nuclear antigens
Poststreptococcal
glomerulonephritis
Streptococcal cell wall antigen(s);
may be "planted" in glomerular
basement membrane
Nephritis
Polyarteritis nodosa
Reactive arthritis
Serum sickness
Hepatitis B virus antigen
Bacterial antigens (Yersinia )
Various proteins, such as foreign
serum protein (horse anti-thymocyte
globulin)
Systemic vasculitis
Acute arthritis
Arthritis, vasculitis,
nephritis
Arthus reaction
(experimental)
Various foreign proteins
Cutaneous vasculitis
Type IV Hypersensitivity
(Cell mediated type)
• Delayed Type Hypersensitivity (DTH) - CD4+ T cell
mediated macrophage and endothelial activation
• Granulomatous inflammation - continual T cell drive
with lack of complete M digestion of Ag
• Cytolytic T Lymphocytes (CTL) - direct lysis of target
cells involving TCR recognition at effector phase
• NK cell activity - no specific recognition (no TCR).
Require IL-2 and perhaps other cytokines.
• Technical difficulties in experimental determination of
cellular vs Ab mediated immune mechanisms.
Granulomatous
Inflammation
• Aggregation of
macrophages with fibrosis
• Associated with chronic T
cell and macrophage
activation
• Antigen that is resistant to
macrophage degradation
Examples of T-Cell-Mediated (Type IV) Hypersensitivity
Disease
Type 1 diabetes
mellitus
Specificity of Pathogenic T cells
Antigens of pancreatic islet βcells
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Clinicopathologic
Manifestations
Insulitis (chronic inflammation in
islets), destruction of βcells;
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Multiple sclerosis
Protein antigens in CNS myelin (myelin Demyelination in CNS with
basic protein, proteolipid protein)
perivascular inflammation;
paralysis, ocular lesions
Rheumatoid arthritis
Unknown antigen in joint synovium
(type II collagen?); role of antibodies?
Chronic arthritis with
inflammation, destruction of
articular cartilage and bone
Peripheral neuropathy;
Guillain-Barré
syndrome?
Inflammatory bowel
disease (Crohn's
disease)
Protein antigens of peripheral nerve
myelin
Neuritis, paralysis
Contact dermatitis
Environmental chemicals, e.g., poison
ivy (pentadecylcatechol)
Unknown antigen; may be derived from Chronic inflammation of ileum
intestinal microbes
and colon, often with
granulomas; fibrosis, stricture
Dermatitis, with itching; usually
short-lived, may be chronic with
persistent exposure
Relationship of antibody vs cell
mediated hypersensitivity
• Radical difference in assay/detection
methodology
• Usually both are present in a strong immune
response
• Presence of antibody can be a marker of a
specific T cell mediated lesion
• Passive transfer is the key experimental
approach to determine primary cause of
response.
Classification Scheme
Mechanism vs Antigen
• Classical system focuses on mechanism
– Don’t know all mechanisms (especially early)
– Actual disease mechanisms overlap
• Alternative system focused on antigen drive
– The kinetic course of antigen concentration is the
key immunoregulatory entity.
– Often don’t know the specific driving antigens
– Infection, environmental, tumors, iatrogenic, self.
Leprosy
• Two forms of disease; one bug
(Mycobacterium leprae).
• Tuberculoid leprosy - intense immune
response with low organism load
• Lepromatous leprosy - suppressed immune
response with high organisms load
• Different cytokine patterns in T cell
response correlate with forms of disease
Contact Dermatitis
• Exposure of the skin to multiple agents can cause
sensitization. On repeated exposure, an
eczematous eruption occurs.
• Histologically, the lesion is a mononuclear
infiltrate, epidermal spongiosis (intercellular
edema), and vesicle formation (bullae).
• Depends on ability covalently conjugate to
proteins.
• Exposure to poison ivy is a common example of
this process.
Penicillin Allergy
• Since penicillin is fairly reactive with proteins,
sensitization is common.
• Depending on the idiosyncratic nature of the immune
response and subsequent exposure, several clinical
syndromes may develop.
• Formation of IgE can result in systemic anaphylaxis after
penicillin therapy (particularly after intravenous
administration).
• Formation of IgG and drug conjugates of serum proteins
(albumin) can lead to a "serum sickness" syndrome,
involving fever, skin rash, lymphadenopathy, and edema.
Occasionally arthritis, nephritis, and vasculitis may result.
• Conjugation to red blood cells with high dose IV therapy
and IgG formation can result in development of hemolytic
anemia.
Tumor Antigens for CD8+ T cells
Organ/Tissue Transplants
Alloantigen Recognition
Direct
Presentation
Indirect
Presentation
Recipient
APC
Donor
APC
Many
endogenous
peptides
T
Donor
peptide
T
Recipient T cells
Mechanisms of transplant rejection
(classical)
• No “real” physiologic mechanism
(evolutionarily selected)
• Hyperacute rejection
• Acute vascular rejection
• Acute cellular rejection
• Chronic rejection
Mechanisms of transplant rejection
• Cytotoxic damage to endothelial cells with
coagulation
• “DTH” in interstitium - CD4+ T cells & M
activation
• CTL activity on parenchymal cells (tubules,
cardiomyocytes, bile ducts, hepatocytes)
• T cell mediated arteritis with intimal proliferation
and infarction
• ADCC and NK cell activity in interstitium
• Antibody mediated injury to endothelia with
intimal proliferation and infarction
Clinical Monitoring of Allograft Rejection
•
•
•
•
•
Kidney - serum creatinine/Biopsy
Heart - Blind Biopsy
Liver - Bilirubin, transaminases/Biopsy
Lung - Pulmonary Function tests/Biopsy
Pancreas - No good method, (urinary
amylase, or cytology)
IgE
Ab
Immune
Complex
T cells