Diseases of the immune

system

Lecture I.
Ágota Szepesi
I. Department of Pathology
 The normal immune response
Innate immunity (natural, native)
immediate response to infections

NOT SPECIFIC
NO ADAPTATION- same intensity on repeated
exposures

Adaptive immunity (acquired, specific)

immediate to late response to

infection

HIGHLY SPECIFIC
ADAPTATION-improved response
MEMORY
 Adaptive immunity
Humoral immunity: Cellular immunity:
Effectors: B-cells, antibodies Effectors:T lymphocytes
Role: protection against Role: protection against
extracellular microbes intracellular microbes

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 B-cell function
Immunglobulin (antibody) production

SPECIFICITY- Immunglobulin gene rearrangement

Somatic hypermutation
 B-cell development
Bone marrow Secondary lymphoid organs

Naiv B cells
Ig rearangement

MEMORY- memory B cells

 T cell development
Thymus Secondary lymphoid organs

T-cell receptor
rearrangement

T cells recognize antigens only in association

with MHC molecules- MHC restriction
 T-cell function
CD4+ helper T cells- CD8+ cytotoxic T cells-
recognize peptides-deriving from recognize intracellular
extracellular microbes- on APC in peptide antigens- tumor
association with MHC II cells/ viral antigens in
association with MHC I
Regulation of the immune response
• Activation of innate and specific immunity by
T cells
• Duration and intensity is regulated by
cytokines proguced by T cells and
macrophages
• Genetic control- MHC haplotype controls
antigen recognition by T-cells
– Genetic predisposition to pathological
immune reactions is MHC associated
• Memory-long lived memory cells- antigen
specific B lymphocytes
 Diseases involving the immune
system

• Hypersensitivity, allergy
• Autoimmune diseases
• Immunodeficiencies
• Transplantation pathology
• Amyloidosis
 Hypersensitivity reactions

• Abnormal/excessive immune responses in

sensitized individuals=ALLERGY
• Difficult to control or terminate-
– immune-mediated injury to host tissues
– chronic inflammatory reaction
• Association with inheritence of specific
susceptibility genes – MHC/HLA genes
 Types of hypersensitivity reactions
• Classification is based on the mechanism
of immune injury
• Type I-III antibody mediated

• Type IV cell mediated

• Antigen- ALLERGEN
 Type I
Immediate hypersensitivity
• Sensitization (antibody
production) against
environmental antigens
(allergens: pollens, house
dust)
• Immediate reaction in
minutes
• IgE antibody mediated
• Main effector cells: Mast
cells
• Late phase: tissue
infiltration by eosinophils,
neutrophils
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• Mast cell mediators:
– Vasoactive amines released from granule
stores- HISTAMINE
– Newly synthesized lipid mediators:
PROSTAGLANDINS, LEUKOTRIENES
– Cytokines: TNF, PAF, CHEMOKINS
• Action:
– Vasodialatation, increased vascular
permeability
– Smooth muscle spasm
– Cellular reaction
Tissue reactions in type I
hypersensitivity

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 Extension of the reaction

• Depending on the portal of entry of

the allergen

– Local: entry through skin, mucous

membranes (respiratory tract, GI tract)
– Systemic reaction = anaphylaxis, due
to blood injection of the allergen
 Local immediate hypersensitivity
• Skin
– Urticaria (hives, nettle rash)

– Allergens:
• GI: drugs (penicillin), food (milk,eggs),
• contact allergens: chemicals, metals
 Local immediate hypersensitivity

• Respiratory tract: nose, sinuses

– Hay fever/ allergic rhinitis, sinusitis
• Serous exudate
• Chronic allergic sinusitis-sinusitis polyposa
• Secundary bacterial sinusitis
Allergens: pollen (ragweed), house
dusts (mite,tick), animal dander, and
food.
• Eye: allergic conjunctivitis
Allergic nasal polyps
Asthma bronchiale
Clinical symptoms due to airway obstruction

Immediate reaction:
oedema, smooth muscle spasm

Late phase: increased

mucus production, smooth
muscle hypertrphy.
Cellular reaction:
infiltration by eosinphils

Allergens: dusts,
pollen, animal dander,
and foods
 Systemic hypersensitivity=Anaphylaxis
• Vascular reaction: severe hypotension,
Circulatory collapse
• systemic vasodilatation, increased vascular
permeability
• tissue hypoperfusion, severe hypoxia
• Skin: itching, urticaria, erythema
• Respiratory tract: difficulty in breathing
• Contraction of respiratory bronchioles, mucus
secretion
• Laryngeal oedema
• Allergens: foreign proteins (vaccine), drugs (antibiotics),
food allergens (peanut), insect toxins (bee venom)
 Type II
Antibody mediated hypersensitivity
• Antibodies bind to cell surface antigen
A. Opsonization, cytolysis and phagocytosis

-Transfusion reaction (A,B, Rh)

- Hemolytic disease of the newborn (anti-Rh)
- Autoimmune cytopenias: hemolytic anemia (AIHA),
immun trombocytopenia (ITP)
 Hemolytic disease of the newborn
IgG molecules against Rh blood group antigens, produced by
the Rh-, sensitized mother, pass through the placenta

Severe hemolysis, hypoxia: Mild hemolysis:

Hydrops fetalis Erythroblastosis fetalis

Erythroid regeneration: erythroblasts

, reticulocytes in the circulation
B. Antibodies bind to cell surface RECEPTORS
influencing cell functions:
Graves disease, diffuse goiter
-Stimulating antibodies against TSH receptors of the
thyroid gland.
Myastenia gravis

Inhibiting antibodies against the acetylcoline

receptors at the neuromuscular junction.
Symptoms: muscle weakness, ptosis, dyplopia

-diplopia

Associated: thymus hyperplasia or thymoma

 Autoimmune gastritis/anaemia perniciosa
– Antibodies against gastric parietal cells/ intrinsic
factor-
– Inhibiting the intrinsic factor-B12 complex ileal
absorbtion
• Chronic atrophic gastritis Normal B12 absorbtion

– Atrophy and lymphocytic

infiltration

– Increased risk of
gastric carcinoma
• Vitamine B12 defficiency
 Vitamin B12 deficiency
• Bone marrow: Megaloblastic erythroid hyperplasia
– Impared DNA synthesis- Cytoplasmic-nuclear asyncrony
– Ineffective erythropoesis
• Perypheral blood: Macrocytic anaemia

• Peripheral neuropathy: due to demyelination of the

spinal cord tracts

• Atrophic glossitis
 Goodpasture syndrome

• Anti-basal membrane antibodies (type IV

collagen)
• Organs: kidney, lung
Haemorrhagic interstitial pneumonitis

Chronic glomerulonephritis
 Pemphigus vulgaris, pemhigoid
• Vesiculo-bullosus disease of the skin and oral
mucosa
• Antibodies (IgG) against the desmosome
proteins
• Acantholysis- suprabasal, subepidermal
 Type III
Immuncomplex mediated hypersensitivity
• Systemic: antigen-antibody complexes are formed in
the circulation in large amount and deposited in blood
vessels
• Local: complexes are formed and deposited in a specific
site.
Antigen:
1. exogenous- microbial proteins- postinfectious
glomerulonephritis-streptococcus, hepatitis B,
treponema pallidum
2. endogenous (nucleoproteins)=self antigens-
autoimmun disease - SLE
 Vasculitis
Mechanism: immune complex
deposition- complement and
neutrophil, monocyte activation
and acute inflammation

Organs involved: kidneys,

joints, skin and small blood
vessels in many tissues.

kidney- glomerulonephritis
joints- arthritis

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 Histology: Fibrinoid necrosis

Consequences:
thrombosis of the
small vessels,
tissue ischemia,
necrosis
Post-streptococcal acut glomerulonephritis
• 1-4 week after β-hemolytic streptococcal infection
• nephritic syndrom
• antibodies to streptococcal antigens (streptolysin O
or DNAase)

-Granular deposition
of IgG and
complement

subepithelial "hump"
(arrow) and
intramembranous deposits
 Rheumatic fever
• Post-streptococcal secondary, immun-mediated
disease
• Diagnosis: Jones criteria (5)
– Pancarditis- Mechanism: type II hypersensitivity by
antibody mimicry, crossreaction between stretococcal
and fixed cardiac antigens
– Polyarthitis:Mechanism: type III
hypersensitivity=immun-complex deposition.
Migratory, serous inflammation of the large joints
– Subcutanous rheumotoid nodules
– Erythema marginatum
– Chorea minor
 Heart- pancarditis
Acut phase: pancarditis

1.Acut fibrinous pericarditis

2.Granulomatous myocarditis: Aschoff body

Anitschkow cells
3.Acut endocarditis:

vegetations

Chronic phase: Mitral stenosis

chronic endocarditis thickening and
Aortic and mitral valves distortion of the
cusps with
commissural fusion
 Type IV
Delayed type Hypersensitivity (DTH)
Cell mediated:
T cells,
macrophages
against intracellular
pathogens,
(mycobacteria,
viruses, fungi,
parasites).

Figure 5-13 Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions. A, In delayed-type hypersensitivity reactions, CD4+ T cells (and sometimes CD8+ cells)
respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. B, In some diseases, CD8+ CTLs directly
kill tissue cells. APC, antigen-presenting cell.
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 Tuberculin reaction
CD4+ T cell mediated
due to the circulating
memory T cells specific
for mycobacterial
proteins

-screening populations
for tuberculosis

Macroscopy: erythema
and induration
(dermal edema and
fibrin deposition )
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 Granulomatous inflammation

Prolonged DTH reactions

persistent stimuli

After 2-3 weeks- granuloma

formation:
Epitheloid cells: activated
tissue macrophages
Langhans type giant cells:
epitheloid cell fusion
Lymphocytes-T-cells
Fibrous capsule – in old
granulomas

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 Granulomatous inflammation
• Infectious granulomas:
– Tuberculosis
– Syphilis
– Fungal, parasitic infections

• Non-infectious granulomas
– Rheumatic fever- Aschoff granuloma-
– Sarcoidosis
– Crohn disease
– Foreign body granulomas
 Contact dermatitis/ ekzema
Allergen- exogen (poison ivy, poison oak)
Antigen presentation by Langerhans cells
CD4+ cell response (48-72 hours) - activation of
macrophages and keratinocytes-
Histology: Macrophage and T cell and eosinophil cell
infiltration
Damage to keratinocytes- intraepidermal vesicle formation.
 T-Cell-Mediated Cytotoxicity

• Effector cells: CD8+T cells.

• Antigens are intracellular
• Mechanism: Perforin-granzyme system- activating the
caspase system leading to apoptosis
• Roles
– Killing of viral infected cells
– Anti-tumor immunity
– Rejection of solid-organ transplants
– Autoimmune diseases-against self antigens
Histological findings in hypersensitivity
reactions

I. III. IV.
 Amyloidosis

• Extracellular aggregation
and deposition of fibrillary
misfolded proteins
• Biochemically distinct 20
proteins with similar
structure:β-sheet
polypeptide chains
• Diagnosis: histology,

7.5-10 nm amyloid fibrils

 Classification of amyloidosis
I. Systemic
• Primary- plasma cell neoplasia- AL amyloid
• Secondary-chronic inflammation-SAA amyloid
• Osteomyelitis, bronchiectasy, tuberculosis
II. Localized
Brain-Alzheimer disease- A amyloid
Endocrine- thyroid medullary cancer- calcitonin

Hereditary (familiar): mutation of Transtiretin-

transport protein for thiroxin, retinol
Senile- transtiretin (heart)
Organ involvement: Kidney,
spleen, liver, GI, heart,

Macroscopic picture: large,

light organs

Kidney: chronic renal failure

Heart: restrictive type cardiomyopathy

Macroscopic detection: Lugol solution: cut organ is painted

with iodine and sulfuric acid. This yields mahogany brown staining of the
amyloid deposits
Microscopic detection: congo red stainig

Congo red Polarization microscopy:

green birefringence

Diagnosis is based on histology!!

 Amyloidosis- tongue, gingiva

macroglossia Plasma cell tumor

Thank You!